cholecalciferol and Breast-Neoplasms

The active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is primarily known as a key regulator of calcium and phosphate homeostasis. It exerts its biological functions by binding to the vitamin D receptor (VDR), a transcription factor that regulates gene expression in vitamin D-target tissues such as intestine, kidney and bone. Yet, the VDR is expressed in many additional normal and cancerous tissues, where it moderates the antiproliferative, prodifferentiating and immune-modulating effects of 1,25(OH)2D3. Interestingly, several epidemiological studies show that low levels of 25(OH)D, a biological marker for 1,25(OH)2D3 status, are associated with an increased risk of breast cancer (BC) development. Mendelian randomization studies, however, did not find any relationship between single-nucleotide polymorphisms in genes associated with lower serum 25(OH)D and BC risk. Nevertheless, multiple and in vivo preclinical studies illustrate that 1,25(OH)2D3 or its less calcaemic structural analogues influence diverse cellular processes in BC such as proliferation, differentiation, apoptosis, autophagy and the epithelial-mesenchymal transition. Recent insights also demonstrate that 1,25(OH)2D3 treatment impacts on cell metabolism and on the cancer stem cell population. The presence of VDR in the majority of BCs, together with the various anti-tumoural effects of 1,25(OH)2D3, has supported the evaluation of the effects of vitamin D3 supplementation on BC development. However, most randomized controlled clinical trials do not demonstrate a clear decrease in BC incidence with vitamin D3 supplementation. However, 1,25(OH)2D3 or its analogues seem biologically more active and may have more potential anticancer activity in BC upon combination with existing cancer therapies.

Topics: Breast; Breast Neoplasms; Cholecalciferol; Female; Humans; Receptors, Calcitriol; Vitamin D; Vitamins

Dietary vitamin D3 has attracted wide interest as a natural compound for breast cancer prevention and therapy, supported by in vitro and animal studies. The exact mechanism of such action of vitamin D3 is unknown and may include several independent or partly dependent pathways. The active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D, calcitriol), binds to the vitamin D receptor (VDR) and induces its translocation to the nucleus, where it transactivates a myriad of genes. Vitamin D3 is involved in the maintenance of a normal epigenetic profile whose disturbance may contribute to breast cancer. In general, the protective effect of vitamin D3 against breast cancer is underlined by inhibition of proliferation and migration, stimulation of differentiation and apoptosis, and inhibition of epithelial/mesenchymal transition in breast cells. Vitamin D3 may also inhibit the transformation of normal mammary progenitors into breast cancer stem cells that initiate and sustain the growth of breast tumors. As long noncoding RNAs (lncRNAs) play an important role in breast cancer pathogenesis, and the specific mechanisms underlying this role are poorly understood, we provided several arguments that vitamin D3/VDR may induce protective effects in breast cancer through modulation of lncRNAs that are important for breast cancer pathogenesis. The main lncRNAs candidates to mediate the protective effect of vitamin D3 in breast cancer are

Topics: Animals; Breast Neoplasms; Calcitriol; Cholecalciferol; Female; Humans; Receptors, Calcitriol; RNA, Long Noncoding; Signal Transduction; Vitamin D; Vitamins

The biologically active form of vitamin D

Topics: Animals; Breast Neoplasms; Cholecalciferol; Disease Models, Animal; Female; Humans; Mice; Mice, Transgenic; Vitamins

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

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The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3 or calcitriol), is known to inhibit the proliferation and invasiveness of many types of cancer cells, including breast, colon, pancreatic, prostate, and liver cancer cells. These findings support the use of 1α,25(OH)2D3 for the treatment of these types of cancer. However, 1α,25(OH)2D3 can cause hypercalcemia, so analogs of 1α,25(OH)2D3 that are less calcemic but exhibit more potent anti-tumor activity would be good candidates as therapeutic agents. Therefore, a series of 19-norvitamin D analogs, in which the methylidene group on C19 is replaced with 2 hydrogen atoms, have been synthesized by several laboratories. In our laboratory, we have designed and synthesized a series of 2α-functional group substituted 19-norvitamin D3 analogs and examined their anti-proliferative activity. Among them, 2α- and 2β-(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D3 (MART-10 and MART-11) were found to be the most promising. Here, we review the rationale and approaches for the synthesis of different 19-norvitamin D analogs, and the pre-clinical studies using these analogs in breast cancer cells, in particular, we chose MART-10 for its potential application to the prevention and treatment of breast cancer.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cholecalciferol; Female; Humans; Receptors, Calcitriol

Vitamin D is not really a vitamin but the precursor to the potent steroid hormone calcitriol, which has widespread actions throughout the body. Calcitriol regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis. Although epidemiological and early clinical trials are inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for vitamin D, accumulating results from preclinical and some clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Breast Neoplasms; Calcitriol; Cholecalciferol; Colonic Neoplasms; Disease Progression; Endocrine System; Female; Humans; Male; Neoplasms; Neoplastic Stem Cells; Polymorphism, Genetic; Prognosis; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk; Signal Transduction; Steroid Hydroxylases; Vitamin D; Vitamin D Deficiency; Vitamin D3 24-Hydroxylase

Vitamin D3 deficiency is rampant which may contribute to increased risk of many diseases including cancer, cardiovascular disease and autoimmune disorders. Genomic activity of the active metabolite 1,25-dihydroxyvitamin D (1,25D) mediates most vitamin D3's actions and many gene targets of 1,25D have been characterized. As the importance of non-coding RNAs has emerged, the ability of vitamin D3via 1,25D to regulate microRNAs (miRNAs) has been demonstrated in several cancer cell lines, patient tissue and sera. In vitamin D3 intervention patient trials, significant differences in miRNAs are observed between treatment groups and/or between baseline and followup. In patient sera from population studies, specific miRNA differences associate with serum levels of 25D. The findings thus far indicate that dietary vitamin D3 in patients and 1,25D in vitro not only regulate specific miRNA(s), but may also globally upregulate miRNA levels. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Topics: Breast Neoplasms; Calcitriol; Cholecalciferol; Colonic Neoplasms; Female; Humans; Leukemia; Male; Melanoma; MicroRNAs; Neoplasms; Prostatic Neoplasms

Radiation has long been a useful component of the treatment regimen for solid tumors. However, some malignancies are relatively resistant to radiation treatment while even tumors that may initially respond (to both radiation and chemotherapy) may eventually recover proliferative capacity. A variety of approaches have been utilized in the efforts to enhance radiation sensitivity. Recent studies have identified autophagy as a cell death pathway that may mediate the radiosensitizing effects of selected treatments. Studies in our laboratory support the premise that radiosensitization of breast tumor cells by vitamin D or vitamin D analogs is mediated through autophagy. In addition, promotion of autophagic cell death by a vitamin D analog in irradiated breast tumor cells delays and attenuates the proliferative recovery that may be a preclinical indicator of disease recurrence.

Topics: Apoptosis; Autophagy; Breast Neoplasms; Cell Line, Tumor; Cholecalciferol; DNA Damage; DNA Repair; Female; Humans; Radiation Tolerance; Radiation, Ionizing; Sensitivity and Specificity

The vitamin D-3 receptor (VDR) is a nuclear receptor that modulates gene expression when complexed with its ligand 1-alpha,25-dihydroxycholecalciferol [1,25(OH)(2)-D(3)], which is the biologically active form of vitamin D-3. The cellular effects of VDR signaling include growth arrest, differentiation and/or induction of apoptosis, which indicate that the vitamin D pathway participates in negative-growth regulation. Although much attention has been directed in recent years toward the development of synthetic vitamin D analogs as therapeutic agents for a variety of human cancers including those derived from the mammary gland, studies on vitamin D as a chemopreventive agent for breast cancer have been quite limited. The VDR is expressed in normal mammary gland, where it functions to oppose estrogen-driven proliferation and maintain differentiation; this suggests that 1,25(OH)(2)-D(3) participates in negative-growth regulation of mammary epithelial cells. Furthermore, preclinical studies show that vitamin D compounds can reduce breast cancer development in animals, and human data indicate that both vitamin D status and genetic variations in the VDR may affect breast cancer risk. Collectively, findings from cellular, molecular and population studies suggest that the VDR is a nutritionally modulated growth-regulatory gene that may represent a molecular target for chemoprevention of breast cancer.

Topics: Animals; Breast; Breast Neoplasms; Cholecalciferol; Female; Humans; Male; Mammary Neoplasms, Animal; Mice; Mice, Knockout; Molecular Biology; Receptors, Calcitriol; Tumor Cells, Cultured; Vitamin D

1,25-dihydroxyvitamin D3[1,25(OH)2D3] is a well-known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH)2D3 involves 25- and 1 alpha-hydroxylation of vitamin D3, in the liver and kidney, respectively, of absorbed or skin-synthesized vitamin D3. There is recent focus on the importance in growth control of local metabolism of 1,25(OH)2D3, which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24-hydroxylase. The classical signalling pathway of 1,25(OH)2D3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH)2D3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis. 1,25(OH)2D3 has a major inhibitory effect on the G1/S checkpoint of the cell cycle by upregulating the cyclin dependent kinase inhibitors p27 and p21, and by inhibiting cyclin D1. Indirect mechanisms include upregulation of transforming growth factor-beta and downregulation of the epidermal growth factor receptor. 1,25(OH)2D3 may induce apoptosis either indirectly through effects on the insulin-like growth receptor and tumour necrosis factor-alpha or more directly via the Bcl-2 family system, the ceramide pathway, the death receptors (e.g. Fas) and the stress-activated protein kinase pathways (Jun N terminal kinase and p38). Inhibition of tumour invasion and metastasis potential has been demonstrated and mechanisms include inhibition of serine proteinases, metalloproteinases and angiogenesis. The lines of evidence for an effect of vitamin D3 in systemic cancer are the laboratory demonstration of relevant effects on cellular growth, differentiation, apoptosis, malignant cell invasion and metastasis; epidemiological findings of an association of the occurrence and outcome of cancers with derangements of vitamin D3/1,25(OH)2D3 and the association of functional polymorphisms of the VDR with the occurrence of certain cancers. In addition, vitamin D3 analogues are being developed as cancer chemotherapy agents. There is accumulating evidence that the vitamin D3/1,25(OH)2D3/VDR axis is similarly important in malignant melanoma (MM). MM cells express

Topics: Breast Neoplasms; Cell Differentiation; Cell Division; Cholecalciferol; Colonic Neoplasms; Female; Humans; Male; Melanoma; Polymorphism, Genetic; Prostatic Neoplasms; Receptors, Calcitriol; Signal Transduction; Skin; Skin Neoplasms; Vitamin D

The etiology, pathophysiology, and diagnosis of hypercalcemia associated with malignant diseases are discussed. In humans, calcium is controlled by three mechanisms: parathyroid hormone, which regulates bone resorption and renal reabsorption of calcium; calcitonin, an antagonist of parathyroid hormone; and cholecalciferol, which regulates calcium absorption from the gastrointestinal tract. Hypercalcemia of malignancy (HCM) results primarily from increased bone resorption by osteoclasts and, to a lesser extent, from increased renal tubular reabsorption. In most tumors, parathyroid hormone-related protein (PTHrP) is the primary mediator of calcium. PTHrP stimulates increased bone resorption by osteoclasts. This stimulation also activates transforming growth factor-beta (TGF-beta), which stimulates tumor cells, thus perpetuating the cycle. Hypercalcemia is usually defined as a serum calcium concentration greater than 12 mg/dL, corrected for the serum albumin concentration. In diagnosing HCM, it is important to rule out other causes of hypercalcemia, such as primary hyperparathyroidism.

Topics: Bone Resorption; Breast Neoplasms; Calcitonin; Calcium; Cholecalciferol; Female; Hematologic Neoplasms; Homeostasis; Humans; Hypercalcemia; Kidney; Lung Neoplasms; Male; Multiple Myeloma; Neoplasms; Parathyroid Hormone

Promotion of apoptosis (which is frequently dependent on functional p53) is thought to be critical for the effectiveness of chemotherapy or radiotherapy. Studies in this as well as other laboratories have demonstrated that breast tumor cells are relatively refractory to apoptosis in response to modalities that induce DNA damage. This report describes our efforts to understand the basis for the absence of an apoptotic response to adriamycin and ionizing radiation in the breast tumor cell based on alterations in cell-cycle and apoptotic regulatory proteins. We also report on the permissive effects of Vitamin D3 and the Vitamin D3 analog EB 1089 in the promotion of apoptosis in p53-wild-type cells. Our studies suggest that regulation of apoptosis in the breast tumor cell may require modulation of signaling events other than or in addition to the p53-dependent DNA damage response.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Calcitriol; Cell Cycle; Cell Division; Cholecalciferol; DNA Damage; Enzyme Inhibitors; Female; Humans; Radiation, Ionizing; Topoisomerase II Inhibitors; Tumor Cells, Cultured

Topics: Apoptosis; Breast Neoplasms; Cell Differentiation; Cell Division; Cholecalciferol; Drug Resistance; Estrogen Antagonists; Female; Humans; Neoplasms, Hormone-Dependent; Tumor Cells, Cultured

In this review I summarize the experimental data in favor of the notion that control of epidermal growth factor (EGF) receptor (R) and/or c-erbB-2 protooncogene expression by specific autocrine growth factors and certain classical endocrine hormones serves as a transducer of extracellular signals that ultimately lead to growth responses in breast carcinoma cells. I summarize some new results on the role of epidermal growth factor (EGF), transforming growth factor (TGF) alpha, and TGF beta in the control of EGF-R protooncogene expression in human breast carcinoma cells. Furthermore, the data embracing the hypothesis that the growth actions of hormone receptors that are homologous to the v-erbA oncogene (estrogens, progesterone, thyroid hormones, retinoic acid, and vitamin D) are mediated, in part, by modulating EGF-R and/or c-erbB-2 protooncogene transcription are reviewed. Finally, I develop the theme that cooperation of certain c-erb-A-related, c-erbB-2 and/or EGF-R gene products contribute to the uncontrolled growth of human mammary carcinoma cells. From the evidence reviewed, one can infer that elucidation of the molecular control of EGF-R/c-erbB-2 gene expression by c-erbA-related gene products may lead to both a better understanding of breast carcinogenesis and a new therapeutic approach directed at controlling the transcriptional responses of EGF-R/c-erbB-2 genes.

Topics: Biomarkers, Tumor; Breast Neoplasms; Cell Division; Cholecalciferol; Epidermal Growth Factor; ErbB Receptors; Estrogens; Gene Expression Regulation, Neoplastic; Humans; Hydrocortisone; Progesterone; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-myc; Receptor, ErbB-2; Transforming Growth Factor alpha; Transforming Growth Factor beta; Tretinoin; Triiodothyronine

The effect of calcium plus vitamin D (CaD) supplementation on risk of ductal carcinoma in situ (DCIS) of the breast, a nonobligate precursor of invasive ductal carcinoma, is not well understood. In this secondary analysis, we examined this association in the Women's Health Initiative CaD trial over approximately 20 years of follow-up.. A total of 36 282 cancer-free postmenopausal women (50-79 years) were randomly assigned to daily (d) calcium (1000 mg) plus vitamin D (400 IU) supplementation or to a placebo. Personal supplementation with vitamin D (≤600 IU/d, subsequently raised to 1000 IU/d) and calcium (≤1000 mg/d) was allowed. The intervention phase (median = 7.1 years), was followed by a postintervention phase (additional 13.8 years), which included 86.0% of the surviving women. A total of 595 incident DCIS cases were ascertained. Hazard ratios (HRs) plus 95% confidence intervals (CIs) were calculated.. The intervention group had a lower risk of DCIS throughout follow-up (HR = 0.82, 95% CI = 0.70 to 0.96) and during the postintervention phase (HR = 0.76, 95% CI = 0.61 to 0.94). The group that used CaD personal supplements in combination with the trial intervention had a lower risk of DCIS compared with the trial placebo group that did not use personal supplementation (HR = 0.72, 95% CI = 0.56 to 0.91).. CaD supplementation in postmenopausal women was associated with reduced risk of DCIS, raising the possibility that consistent use of these supplements might provide long-term benefits for the prevention of DCIS.

Topics: Aged; Breast Neoplasms; Calcium Carbonate; Carcinoma, Intraductal, Noninfiltrating; Cholecalciferol; Confidence Intervals; Female; Follow-Up Studies; Humans; Incidence; Kaplan-Meier Estimate; Middle Aged; Placebos; Postmenopause; Proportional Hazards Models; Risk; Time Factors; Vitamins

The aim of this study was to investigate the effects of cholecalciferol supplementation on serum levels of angiogenic parameters in patients with breast cancer (BC) who were treated with tamoxifen.. This was a pilot-based, randomized, triple-blind, placebo-controlled clinical trial with 52 patients with BC randomly assigned to either an intervention group receiving weekly 50 000 IU cholecalciferol or a placebo group for 8 wk. At baseline and at end of study, serum levels of angiogenic growth factors such as vascular endothelial growth factor (VEGF)-A, angiopoietin (Ang)-2, hypoxia-inducible factor (Hif)-1, and high-sensitivity C-reactive protein were measured by enzyme-linked immunosorbent assay. Every 4 wk, a completed 3-d, 24-h dietary record and daily sunlight exposure checklist were collected and anthropometric variables were measured.. The ultimate number of participants in each arm was 22 for analyses. For premenopausal women, cholecalciferol supplementation resulted in a significant decrease in serum levels of Ang-2 and VEGF-A after 8 wk of treatment (P < 0.05). In the absence of vascular invasion, supplementation led to a significant decrease in Ang-2 levels compared with the placebo group (P < 0.05). Supplementation caused significant increases in Hif-1 in patients diagnosed with the infiltration of tumors into vascular or lymphatic vessels (P < 0.05).. Cholecalciferol supplementation achieved sufficient efficacy among patients with BC taking tamoxifen and could be effective in the reduction of angiogenic biomarkers particularly dependent on the infiltration status of the tumor to vessels. Further studies with larger subgroups should be investigated.

Topics: Adult; Angiopoietin-2; Antineoplastic Agents, Hormonal; Biomarkers; Breast Neoplasms; Cholecalciferol; Dietary Supplements; Double-Blind Method; Female; Humans; Hypoxia-Inducible Factor 1; Middle Aged; Pilot Projects; Postmenopause; Premenopause; Research Design; Tamoxifen; Vascular Endothelial Growth Factor A; Vitamins

We investigated whether vitamin D receptor (VDR) polymorphisms are associated with circulating metabolic biomarkers and anthropometric measures changes in breast cancer survivors supplemented with vitamin D3.. One hundred sixty-eight breast cancer survivors admitted to Shohaday-e-Tajrish hospital received 4000 IU of daily vitamin D3 supplements for 12 weeks. Anthropometric measurements as well dietary, physical activity and plasma metabolic biomarkers assessments were performed before and after intervention. VDR polymorphisms were considered as the main exposures. Multivariate multiple linear regression analyses were used to determine the association between the VDR single-nucleotide polymorphisms (SNPs) and changes in metabolic and anthropometric measures in response to vitamin D3 supplementation.. One hundred twenty-five (85%) women had insufficient and inadequate levels of plasma 25-hydroxy vitamin D (25(OH)D) at baseline. Compared to the AA genotype of the ApaI, the aa category showed greater increase in muscle mass [71.3(10.7131.9)] and higher decrease in LDL-C [- 17.9(- 33.6, - 2.3)] levels after adjustment for potential confounders. In addition, the heterozygous genotype (Bb) of the BsmI VDR was associated with higher increase in WC following vitamin D3 supplementation, compared to BB [2.7(0.1,5.3)]. Haplotype score analyses indicate a significant association between inferred haplotypes from BsmI, ApaI, TaqI and FokI, BsmI and Cdx2 VDR polymorphisms and on-study visceral fat changes.. Findings of this study showed that genetic variation in the VDR gene was associated with changes in cardio-metabolic parameters in breast cancer survivors, supplemented with vitamin D3, results could provide a novel insight into better understanding of which subset of individuals benefit most from normalization of vitamin D status.. This trial has been registered on the Iranian Registry of Clinical Trials (IRCT) under the identification code: IRCT2017091736244N1, registration date: 2017-11-10, http://www.irct.ir/trial/27153 and was approved by the ethics committees of the National Nutrition and Food Technology Research Institute (NNFTRI), Shahid Beheshti University of Medical Sciences (SBMU).

Topics: Adult; Anthropometry; Breast Neoplasms; Cancer Survivors; Cholecalciferol; Cholesterol, HDL; Cholesterol, LDL; Dietary Supplements; DNA Restriction Enzymes; Female; Gene Expression; Genotype; Heterozygote; Humans; Intra-Abdominal Fat; Lipid Metabolism; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Receptors, Calcitriol; Triglycerides; Vitamin D; Waist Circumference

We investigated whether vitamin D receptor (

Topics: Adult; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Cholecalciferol; Female; Haplotypes; Humans; Middle Aged; Polymorphism, Single Nucleotide; Radiotherapy; Receptors, Calcitriol

Half of hormone receptor-positive (HR+) breast cancer patients will develop joint pain, termed aromatase inhibitor-induced arthralgia (AIA), while taking aromatase inhibitor therapy. Though there is no universally accepted effective treatment for AIA, there has been some evidence to support high-dose vitamin D as a treatment.. We randomized post-menopausal women who were beginning adjuvant AI therapy to receive standard-dose vitamin D3 (800 IU daily for 52 weeks), or high-dose vitamin D3 (50,000 IU weekly for 12 weeks, followed by 2000 IU daily for 40 weeks). The primary end point was development of AIA. The trial was designed to enroll 184 patients. This futility analysis was performed after 93 patients were enrolled.. The high-dose vitamin D regimen was effective in raising serum vitamin D levels, but there was no significant difference in development of AIA between the two arms. In the high-dose arm, 25 patients (54%) developed AIA, compared to 27 patients (57%) in the standard-dose arm. The planned futility analysis was positive; thus, the study was terminated. Neither baseline vitamin D nor 12-week vitamin D level was predictive of AIA development.. Although vitamin D levels were increased in the high-dose arm, there was no significant signal for benefit of high-dose vitamin D supplementation for AIA prevention in this unblinded trial. This study, along with several others, implies that vitamin D likely does not play a significant role in AIA for the majority of patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Arthralgia; Breast Neoplasms; Cholecalciferol; Dietary Supplements; Female; Humans; Medication Adherence; Middle Aged; Neoplasm Staging; Risk Factors; Treatment Outcome

Background: Low levels of vitamin D are found in a great part of breast cancer women. Study subjects using vitamin\ D3 supplement had lower rates of cancers and fewer markers of inflammation. Additionally, recent studies demonstrate\ the power of vitamin D supplementation to lower inflammation and oxidative stress biomarkers associate with VDR\ polymorphism to reduce inflammation. This study was aimed to assess the impact of vitamin D3 supplementation on\ the serum concentration of inflammatory markers and antioxidant capacity with regard to VDR polymorphism in the\ VDR gene in breast cancer women. Methods: A randomized, double-blind, placebo-controlled trial was conducted on 56\ breast cancer women. Participants were assigned to 2 treatment arms: placebo and vitamin D3 for 2 months intervention.\ Supplementation group received 50,000 IU of vitamin weekly. Blood samples were collected at baseline and after\ the intervention to measure the 25(OH) D3, TNF-α, TGF- β and TAC. Genotyping was performed for FokI, BsmI, ApaI,\ and TaqI polymorphism. Results: After eight weeks supplementation, the intervention group showed a significant increase\ in the serum concentration of 25(OH) D3 (28±2.6 to 39±3.5; p=0.004 and TAC (48.9±13.3 to 63.5±13.3; p= 0.017).\ Changes in TNF-α, TGF- β1 were not significant. Serum TAC levels of participants with the TT/Tt, Ff genotypes were\ more responsive to supplementation. Conclusions: Supplementation with a vitamin D3 increased the TAC in breast\ cancer women, although it had no effect on inflammatory markers. Serum TAC in the TT/Tt, Ff were more responsive to\ vitamin D supplement compared with those with the FF/ff and tt genotypes.

Topics: Antioxidants; Biomarkers, Tumor; Breast Neoplasms; Cholecalciferol; Dietary Supplements; Double-Blind Method; Female; Follow-Up Studies; Genotype; Humans; Inflammation; Middle Aged; Oxidative Stress; Polymorphism, Genetic; Prognosis; Receptors, Calcitriol; Vitamins

Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) frequently occur in women being treated for breast cancer. Prior studies suggest high prevalence of vitamin D deficiency in breast cancer patients with musculoskeletal (MS) pain. We conducted a randomized, placebo-controlled trial to determine if 30,000 IU vitamin D3 per week (VitD3) would prevent worsening of AIMSS in women starting adjuvant letrozole for breast cancer.. Women with stage I-III breast cancer starting adjuvant letrozole and 25(OH)D level ≤40 ng/ml were eligible. All subjects received standard daily supplement of 1200 mg calcium and 600 IU vitamin D3 and were randomized to 30,000 IU oral VitD3/week or placebo. Pain, disability, fatigue, quality of life, 25(OH)D levels, and hand grip strength were assessed at baseline, 12, and 24 weeks. The primary endpoint was incidence of an AIMSS event.. Median age of the 160 subjects (80/arm) was 61. Median 25OHD (ng/ml) was 25 at baseline, 32 at 12 weeks, and 31 at 24 weeks in the placebo arm and 22, 53, and 57 in the VitD3 arm. There were no serious adverse events. At week 24, 51% of women assigned to placebo had a protocol defined AIMSS event (worsening of joint pain using a categorical pain intensity scale (CPIS), disability from joint pain using HAQ-II, or discontinuation of letrozole due to MS symptoms) vs. 37% of women assigned to VitD3 (p = 0.069). When the brief pain inventory (BPI) was used instead of CPIS, the difference was statistically significant: 56 vs. 39% (p = 0.024).. Although 30,000 IU/week of oral vitamin D3 is safe and effective in achieving adequate vitamin D levels, it was not associated with a decrease in AIMSS events based on the primary endpoint. Post-hoc analysis using a different tool suggests potential benefit of vitamin D3 in reducing AIMSS.

Topics: Administration, Oral; Bone Density Conservation Agents; Breast Neoplasms; Calcium, Dietary; Chemotherapy, Adjuvant; Cholecalciferol; Female; Humans; Letrozole; Middle Aged; Musculoskeletal Pain; Neoplasm Staging; Nitriles; Treatment Outcome; Triazoles

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; 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Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

The purpose of the study was to evaluate the efficacy and safety of vitamin D3 at 4000 IU/day as a treatment option for aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) when compared with the usual care dose of 600 IU D3. We conducted a single site randomized, double-blind, phase 3 clinical trial in women with AIMSS comparing change in symptoms, reproductive hormones and AI pharmacokinetics. Postmenopausal women ≥18 years with stages I-IIIA breast cancer, taking AI and experiencing AIMSS [breast cancer prevention trial symptom scale-musculoskeletal (BCPT-MS) subscale ≥1.5] were admitted. Following randomization, 116 patients had a run-in period of 1 month on 600 IU D3, then began the randomized assignment to either 600 IU D3 (n = 56) or 4000 IU D3 (n = 57) daily for 6 months. The primary endpoint was a change in AIMSS from baseline (after 1 month run-in) on the BCPT-MS (general MS pain, joint pain, muscle stiffness, range for each question: 0 = not at all to 4 = extremely). Groups had no statistically significant differences demographically or clinically. There were no discernable differences between the randomly allocated treatment groups at 6 months in measures of AIMSS, pharmacokinetics of anastrozole and letrozole, serum levels of reproductive hormones, or adverse events. We found no significant changes in AIMSS measures between women who took 4000 IU D3 daily compared with 600 IU D3. The 4000 IU D3 did not adversely affect reproductive hormone levels or the steady state pharmacokinetics of anastrozole or letrozole. In both groups, serum 25(OH)D remained in the recommended range for bone health (≥30 ng/mL) and safety (<50 ng/mL).

Topics: Adult; Aged; Anastrozole; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Arthralgia; Bone Density; Breast Neoplasms; Cholecalciferol; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Letrozole; Middle Aged; Musculoskeletal Diseases; Nitriles; Triazoles; Vitamin D

Vitamin D deficiency (<10ng/mL) and insufficiency (10-30ng/mL) may contribute to musculoskeletal symptoms observed in patients taking letrozole. This study was undertaken to assess the vitamin D status in breast cancer patients who received letrozole for >2months and to see the effects of vitamin D3 and calcium supplementation on them.. Eighty-two breast cancer patients were included. Baseline serum 25-hydroxy vitamin D concentrations were assayed and standard questionnaire was completed. They were given vitamin D3 and calcium supplementation (2000IU/1000 mg and 4000IU/1000mg) based on their baseline serum 25-hydroxy vitamin D concentration for 12weeks.. Baseline serum 25-hydroxy vitamin D concentrations showed that 13.4% of patients were deficient and 73.2% of patients were insufficient in 25-hydroxy vitamin D. There was an increase in the concentrations of calcium, phosphorus and decrease in the concentrations of parathyroid hormone, alkaline phosphatase as the concentration of serum 25-hydroxy vitamin D increases. Patients who received letrozole for a longer duration had a low concentration of serum 25 (OH) vitamin D. Vitamin D3 and calcium supplementation increased the concentrations of calcium, phosphorous and decreased the concentrations of parathyroid hormone and alkaline phosphatase. Patients who had low serum 25-hydroxy vitamin D concentrations had more musculoskeletal symptoms which was improved following supplementation (9.14 vs 8.10 p=0.000).. Vitamin D3 supplementation significantly improved serum 25-hydroxy vitamin D concentrations and decreased letrozole-induced arthralgia.

Topics: Arthralgia; Breast Neoplasms; Calcium; Cholecalciferol; Dietary Supplements; Female; Humans; Letrozole; Middle Aged; Nitriles; Triazoles; Vitamin D

The use of aromatase inhibitor (AI) in postmenopausal women with hormone receptor (HR)-positive early breast cancer (EBC) produces a deleterious effect on bone mass and an increase in fractures. Several studies using intravenous bisphosphonates have shown effective management of AI-induced bone loss. To determine whether a lower dosage in oral form combined with calcitriol can effectively manage AI-induced bone loss, we performed a randomized, double-blind, prospective, placebo-controlled 24-week trial with a combination of alendronate and 0.5-µg of calcitriol daily to HR-positive EBC patients. A total of 98 Korean postmenopausal women with HR-positive EBC who received daily AI, calcium and vitamin D were randomly assigned to 5-mg of alendronate and 0.5-µg of calcitriol (Maxmarvil®) or placebo groups. The bone mineral density (BMD) and turnover markers were measured. At week 24, the difference in lumbar BMD between the groups was 3.0% (p < 0.005). The increase in C-telopeptide after 24 weeks was significantly less in the Maxmarvil group compared to that in the placebo group (35.2 ± 17.5% vs. 109.8 ± 28.6%, p < 0.05). Our study demonstrates that a combination of 5-mg alendronate and 0.5-µg calcitriol is effective to prevent bone loss due to AI in Korean postmenopausal women with EBC.

Topics: Alendronate; Antineoplastic Agents; Aromatase Inhibitors; Biomarkers; Bone and Bones; Bone Density; Bone Density Conservation Agents; Bone Resorption; Breast Neoplasms; Calcitriol; Calcium, Dietary; Cholecalciferol; Collagen Type I; Combined Modality Therapy; Dietary Supplements; Double-Blind Method; Drug Combinations; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Patient Dropouts; Peptides; Postmenopause; Republic of Korea

Calcium and vitamin D may be inversely related to breast cancer risk, in part by affecting mammographic density. However, results from previous, mostly cross-sectional studies have been mixed, and there have been few randomized clinical trials of the effect of calcium and vitamin D supplementation on change in mammographic density.. We assessed the effect of one year of supplementation on mammographic density in 330 postmenopausal women enrolled in the Women's Health Initiative hormone therapy (HT) and calcium and vitamin D (CaD) trials. Women were randomized to receive 1,000 mg/d of elemental calcium carbonate plus 400 IU/d of vitamin D(3) or placebo.. After approximately one year, mammographic density decreased 2% in the CaD supplementation group and increased 1% in the placebo group (ratio of means = 0.97; 95% CI = 0.81-1.17). Results suggested potential interaction by HT use (P = 0.08). Among women randomized to HT placebo, the ratio of mean density comparing CaD supplementation and placebo groups was 0.82 (95% CI = 0.61-1.11) vs. 1.16 (95% CI = 0.92-1.45) in women randomized to active HT. In sensitivity analyses limited to women taking ≥ 80% of study supplements, ratios were 0.67 (95% CI = 0.41-1.07) in women not assigned to HT and 1.07 (95% CI = 0.79-1.47) women assigned to HT.. We observed no overall effect of vitamin D and calcium supplementation on mammographic density after one year.. Potential interaction between these nutrients and estrogen as related to mammographic density warrants further study.

Topics: Aged; Breast; Breast Neoplasms; Calcium, Dietary; Case-Control Studies; Cholecalciferol; Dietary Supplements; Female; Humans; Middle Aged; Postmenopause; Prognosis; Women's Health

Vitamin D deficiency has potential roles in breast cancer etiology and progression. Vitamin D deficiency has also been associated with increased toxicity from bisphosphonate therapy. The optimal dose of vitamin D supplementation is unknown, but daily sunlight exposure can generate the equivalent of a 10,000-IU oral dose of vitamin D(3). This study therefore aimed to assess the effect of this dose of vitamin D(3) in patients with bone metastases from breast cancer.. Patients with bone metastases treated with bisphosphonates were enrolled into this single-arm phase 2 study. Patients received 10,000 IU of vitamin D(3) and 1000 mg of calcium supplementation each day for 4 months. The effect of this treatment on palliation, bone resorption markers, calcium metabolism, and toxicity were evaluated at baseline and monthly thereafter.. Forty patients were enrolled. No significant changes in bone resorption markers were seen. Despite no change in global pain scales, there was a significant reduction in the number of sites of pain. A small but statistically significant increase in serum calcium was seen, as was a significant decrease in serum parathyroid hormone. Treatment unmasked 2 cases of primary hyperparathyroidism, but was not associated with direct toxicity.. Daily doses of 10,000 IU vitamin D(3) for 4 months appear safe in patients without comorbid conditions causing hypersensitivity to vitamin D. Treatment reduced inappropriately elevated parathyroid hormone levels, presumably caused by long-term bisphosphonate use. There did not appear to be a significant palliative benefit nor any significant change in bone resorption.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Bone Neoplasms; Bone Resorption; Breast Neoplasms; Cholecalciferol; Dietary Supplements; Diphosphonates; Female; Humans; Hypoparathyroidism; Middle Aged; Pain

Experimental evidence provides strong support for anti-carcinogenic effects of calcium and vitamin D with respect to breast cancer. Observational epidemiologic data also provide some support for inverse associations with risk. We tested the effect of calcium plus vitamin D supplementation on risk of benign proliferative breast disease, a condition which is associated with increased risk of breast cancer. We used the Women's Health Initiative randomized controlled trial. The 36,282 participants were randomized either to 500 mg of elemental calcium as calcium carbonate plus 200 IU of vitamin D(3) (GlaxoSmithKline) twice daily (n = 18,176) or to placebo (n = 18,106). Regular mammograms and clinical breast exams were performed. We identified women who had had a biopsy for benign breast disease and subjected histologic sections from the biopsies to standardized review. After an average follow-up period of 6.8 years, 915 incident cases of benign proliferative breast disease had been ascertained, with 450 in the intervention group and 465 in the placebo group. Calcium plus vitamin D supplementation was not associated with altered risk of benign proliferative breast disease overall (hazard ratio = 0.99, 95% confidence interval = 0.86-1.13), or by histologic subtype. Risk varied significantly by levels of age at baseline, but not by levels of other variables. Daily use of 1,000 mg of elemental calcium as calcium carbonate plus 400 IU of vitamin D(3) for almost 7 years by postmenopausal women did not alter the overall risk of benign proliferative breast disease.

Topics: Aged; Breast Diseases; Breast Neoplasms; Calcium Carbonate; Cholecalciferol; Dietary Supplements; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Middle Aged; Risk Factors; Vitamins

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Breast Neoplasms; Cholecalciferol; Estrogen Receptor alpha; Female; Humans; Receptors, Calcitriol; Vitamin D; Vitamin D3 24-Hydroxylase

The process of human embryonic mammary development gives rise to the structures in which mammary cells share a developmental lineage with skin epithelial cells such as keratinocytes. As some breast carcinomas have previously been shown to express high levels of involucrin, a marker of keratinocyte differentiation, we hypothesised that some breast tumours may de-differentiate to a keratinocyte-derived 'evolutionary history'. To confirm our hypothesis, we investigated the frequency of involucrin expression along with that of Brk, a tyrosine kinase expressed in up to 86% of breast carcinomas whose normal expression patterns are restricted to differentiating epithelial cells, most notably those in the skin (keratinocytes) and the gastrointestinal tract. We found that involucrin, a keratinocyte differentiation marker, was expressed in a high proportion (78%) of breast carcinoma samples and cell lines. Interestingly, tumour samples found to express high levels of involucrin were also shown to express Brk. 1,25-dihydroxyvitamin D3, a known differentiation agent and potential anti-cancer agent, decreased proliferation in the breast cancer cell lines that expressed both involucrin and Brk, whereas the Brk/involucrin negative cell lines tested were less susceptible. In addition, responses to 1,25-dihydroxyvitamin D3 were not correlated with vitamin D receptor expression. These data contribute to the growing body of evidence suggesting that cellular responses to 1,25-dihydroxyvitamin D3 are potentially independent of vitamin D receptor status and provide an insight into potential markers, such as Brk and/or involucrin that could predict therapeutic responses to 1,25-dihydroxyvitamin D3.

Topics: Breast Neoplasms; Calcitriol; Cholecalciferol; Female; Humans; Neoplasm Proteins; Protein-Tyrosine Kinases; Receptors, Calcitriol

Topics: Breast Neoplasms; Cholecalciferol; Dietary Supplements; Female; Genetic Predisposition to Disease; Humans; Vitamin D; Vitamin D Deficiency

We investigated how vitamin D receptor (

Topics: Alleles; Breast Neoplasms; Cancer Survivors; Cholecalciferol; Dietary Supplements; Female; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Single Nucleotide; Receptors, Calcitriol; Vitamin D

Vitamin D is very important for calcium and mineral metabolism, and many hypotheses appear to link sunlight exposure with cancer risk and prognosis. As many studies supported the antitumor effect of vitamin D we wanted to investigate the potential effect of multiple vitamin D metabolites.. This study compared the anticancer effect of three inactive forms of vitamin D. Broad-spectrum of cytotoxicity with IC. Vitamin D metabolites are a potential option for cancer treatment along with or an alternative to chemo-therapeutics although extensive preclinical studies are required to prove this effect.

Topics: Antineoplastic Agents; Breast Neoplasms; Calcifediol; Cell Line, Tumor; Cholecalciferol; Colorectal Neoplasms; Doxorubicin; Drug Screening Assays, Antitumor; Female; Fibroblasts; Humans; Hydroxycholecalciferols; Inhibitory Concentration 50; MCF-7 Cells; Vitamin D

To assess the potential effect of cholecalciferol supplementation to reduce symptom burden for women with metastatic breast cancer (MBC).. 11 clinically stable women with estrogen receptor-positive MBC were recruited from a single cancer center for this phase 1, nonrandomized study (NCT02186015).. Women with insufficient serum 25-hydroxyvitamin D (25[OH]D) levels qualified to receive high-dose repletion therapy. Clinical and questionnaire data on common symptoms and quality of life were obtained prior to and following supplementation.. Serum 25(OH)D increased significantly pre- versus postintervention. Trends for improvements in endocrine symptoms, bone pain, and fatigue were observed following the intervention.. Women achieved normal serum 25(OH)D levels after eight weeks of supplementation and reported reduced symptom burden. Vitamin D may be a low-cost supportive care therapy; however, future studies should be considered.

Topics: Breast Neoplasms; Cholecalciferol; Dietary Supplements; Female; Humans; Pilot Projects; Quality of Life; Self Report; Vitamin D Deficiency

Targeted delivery of cytotoxic drugs has shown great potential in cancer therapy. In this light, vitamin D3 (vit.D3)-coated micelles were fabricated to encapsulate the cytotoxic drug; etoposide (ETP). Sodium caseinate micelles were first utilized to encapsulate vit.D3 and ETP within their hydrophobic core, then drug-loaded micelles were further decorated with an envelope of vit.D3/ phospholipid complex to enhance the active targeting potency of fabricated micelles via exploiting vit.D3 receptors (VDRs) overexpressed on the outer surface of breast cancer cells. In vitro cytotoxicity studies showed that fabricated micelles exhibited improved anticancer effect on MDA MB-231 and MCF-7 human breast cancer cell lines in comparison to free vit.D3 + ETP without any significant toxicity on normal human lung fibroblast (Wi-38) cells. In vivo biodistribution and efficacy studies in Ehrlich ascites tumor animal model revealed that fabricated micelles manifested improved accumulation in tumor tissue due to active targeting potential of vit.D3 without any remarkable toxicity. More importantly, fabricated micelles resulted in enhanced tumor apoptosis, reduced angiogenesis, invasion and autophagy, besides a decline in the tumor expression levels of both miR-21 and miR-192. Therefore, vit.D3/ETP micelles could serve as a favorable actively targeted anticancer delivery system having a superior effect over the free combination.

Topics: Animals; Breast Neoplasms; Caseins; Cell Line, Tumor; Cholecalciferol; Female; Humans; Micelles; Phospholipids; Tissue Distribution

Treatment of breast cancer by paclitaxel (PAX) often encounters therapeutic failure most likely caused by innate/acquired resistance. Cancer stem cells (CSCs) and multidrug resistance complex (MDR-1 or P-glycoprotein) overexpression are main mechanisms implicated in chemoresistance. Increased aldehyde dehrogenase-1 (ALDH-1) was previously correlated with the stemness features of CSCs and hence is used as a marker for identification and CSCs targeting. The present study, therefore, aimed at investigating the effect of both curcumin (CUR) and vitamin D3 (D3) on MDR-1 and ALDH-1 expression and consequently the resistance to PAX both in vitro and in vivo. CUR was isolated from Turmeric rhizomes and identified using UPLC-ESI-MS/MS. For in vitro studies, the antiproliferative effect of PAX, CUR, 1,25(OH)2D3 (the active form of D3, also known as calcitriol) was determined, each alone and combined (PAX+CUR, PAX+1,25(OH)2D3, and PAX+CUR+1,25(OH)2D3) on MCF-7 breast cancer cells. Ehrlich ascites carcinoma solid tumor animal model was also used for in vivo studies. Combining CUR and/or 1,25(OH)2D3 to PAX showed synergistic cytotoxic interaction on MCF-7 cells. The apoptotic potential was also enhanced, as evidenced by a significant increase in caspase-7 and -9 as well as the pro-apoptotic Bax whereas a decrease in Bcl-2 levels was reported. Combining CUR and 1,25(OH)2D3 to PAX caused a downregulation in both MDR-1 and ALDH-1 gene expression in MCF-7 besides a decrease in their protein levels. In vivo, the triple therapy group (PAX+CUR+D3) showed the least tumor size. It also showed the lowest levels of MDR-1 and ALDH-1. PAX alone, however, showed increased levels of MDR-1 and ALDH-1 compared to control. Overall, the present study showed that PAX, as a monotherapy, demonstrated acquired resistance possibly by increasing MDR-1 expression and enriching CSCs population, as evidenced by increased ALDH-1. However, using CUR and D3 enhanced tumor response to PAX.

Topics: Aldehyde Dehydrogenase 1 Family; Animals; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Cholecalciferol; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; MCF-7 Cells; Mice; Paclitaxel; Receptors, Calcitriol; Retinal Dehydrogenase

Aldehyde dehydrogenase-1 (ALDH-1) is considered a signature of breast cancer stem cells and is linked to poor outcomes in breast cancer patients. This study aimed at investigating the effect of vitamin D3 on enhancing the tumor responsiveness to different conventional chemotherapeutic agents, viz., cisplatin, methotrexate, and doxorubicin.. In vitro and in vivo experiments were performed using combinations of vitamin D3 and chemotherapeutic agents. Cell cycle analysis and apoptosis assays were performed. Moreover, ALDH-1 expression levels were estimated in cancer cell lines and solid tumors. For solid tumors, tumor volume and histopathological necrotic indices were estimated. Leukocyte presence was also evaluated in tumors using leukocyte common antigen (LCA).. Results showed a synergistic interaction between vitamin D3 and each of the chemotherapeutic agents on breast cancer cell lines as well as cell cycle arrest at G2/M phase. A decrease in ALDH-1 levels was reported in both breast cancer cells and in tumor tissues. Reductions in tumor volume were also observed in the groups which received the combination therapy. An influence on necrosis rather than apoptosis was also reported, as evidenced by necrotic indices and Bcl-2 expression in tumor sections, respectively. Increased local leukocytes in tumors was also evident, as indicated by increased expression of leukocyte common antigen (LCA).. Overall, the present study shows that vitamin D3 has an impact on resistance to different chemotherapeutic agents which could be due to the inhibition of ALDH-1, suggesting its use as an adjuvant therapy in cancer patients receiving chemotherapy.

Topics: Aldehyde Dehydrogenase 1 Family; Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Carcinoma, Ehrlich Tumor; Cell Line, Tumor; Cholecalciferol; Cisplatin; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Leukocyte Common Antigens; Methotrexate; Mice; Neoplastic Stem Cells

Dietary patterns are believed to regulate tumor progression by altering the tumor microenvironment. Of note, a high salt diet is a risk factor for various diseases. However, the role of high salt intake in the progression of cancers remains unknown.. We constructed an in vivo high salt diet model in MMTV-PyVT mice with spontaneous tumor-forming properties to explore the role of a high salt diet in the progression of breast cancer as well as the modulation of the tumor microenvironment. Also, in vitro experiments were performed to understand the mechanism.. High salt intake accelerates the growth of breast cancer and facilitates lung metastasis, as well as increases the level of Th17 cells. Increased Th17 cells might promote the growth of breast cancer via the secretion of IL-17F to activate the MAPK signaling pathway in breast cancer cells.

Topics: Animals; Breast Neoplasms; Carcinogenesis; Cholecalciferol; Coculture Techniques; Diet; Female; Humans; Immunity; Lymphocyte Activation; MAP Kinase Signaling System; MCF-7 Cells; Mice; Mice, Transgenic; Neoplasm Metastasis; Sodium Chloride, Dietary; Th17 Cells

We investigated whether plasma oxidative stress and apoptotic biomarkers were associated with the VDR polymorphisms in breast cancer survivors supplemented with vitamin D3. Two hundred fourteen breast cancer survivors received 4000 IU of vitamin D3 daily for 12 weeks. Linear regression was used to analyze whether the effect of vitamin D3 supplementation on response variables was associated with the selected VDR single nucleotide polymorphisms executing by 'association' function in the R package 'SNPassoc'. Linear regression analyses adjusted for age, BMI and on-study plasma 25(OH)D changes indicated that the aa genotype of the ApaI [codominant model (aa vs. AA): -0.21 (-0.39 to -0.03); recessive model (aa vs. AA and Aa): -0.20 (-0.37 to -0.03)] and bb genotypes of the BsmI [recessive model (bb vs. BB and Bb): -0.20 (-0.39 to -0.01)] on VDR were associated with greater decrease in plasma Bcl2. Our findings indicated that, the Ff genotype of FokI was accompanied by higher increase in plasma MDA levels [codominant model (Ff vs. FF): 0.64 (0.18-1.11); dominant model (ff and Ff vs. FF): 0.52 (0.09-0.05)]. This observed association was not remained statistically significant after correction for multiple testing. Haplotype score analyses revealed statistically significant association between the FokI BsmI ApaI haplotype and circulating MDA changes (P-value for global score = 0.001) after false-discovery rate correction. Our study suggests that genetic variations in the VDR do not powerfully modify the effects of vitamin D3 intake on biomarkers associated with antioxidant activity, oxidative stress and apoptosis in breast cancer survivors.

Topics: Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Cancer Survivors; Cholecalciferol; Dietary Supplements; Female; Follow-Up Studies; Humans; Middle Aged; Oxidative Stress; Polymorphism, Single Nucleotide; Prognosis; Receptors, Calcitriol; Vitamin D

Vitamin D3 (vitD3) and its active metabolite, calcitriol (1,25-(OH)

Topics: Breast; Breast Neoplasms; Calcitriol; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Epithelial Cells; Estrogen Antagonists; Estrogens; Female; Humans; Morphogenesis

Low vitamin D levels increase the risk of developing several cancer types including breast cancer. Breast cancer is the most incident cancer among women worldwide and in the United States. Our previous study showed that vitamin D (VD

Topics: Actins; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cholecalciferol; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Hydrogen-Ion Concentration; Hypoxia; MCF-7 Cells; Mechanistic Target of Rapamycin Complex 1; Neoplasm Invasiveness; Neoplasm Metastasis; Proton-Translocating ATPases; Vitamin D

Breast cancer is one of the major causes of death in the USA. Cancer cells, including breast, have high glycolysis rates to meet their energy demands for survival and growth. Vitamin D

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Survival; Cholecalciferol; Enzymes; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Glucose; Glycolysis; Humans; Lactic Acid; MCF-7 Cells; TOR Serine-Threonine Kinases

Cholecalciferol (vitamin D3) is widely supplemented in breast cancer survivors because of the role of vitamin D in multiple health outcomes.. We conducted an observational study in 332 women in Eastern Switzerland with early, i.e., nonmetastatic breast cancer. Tumour-, patient-related and sociodemographic variables were recorded. Cholecalciferol intake and serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were measured at the first visit (baseline) and during a follow-up visit in a median of 210 days (range 87-857) after the first visit. Patients presenting 25(OH)D deficiency were advised to take cholecalciferol supplementation.. At baseline, 60 (18%) patients had 25(OH)D deficiency (≤50 nmol/l, ≤20 ng/l), and 70 (21%) had insufficiency (50-74 nmol/l, 20-29 ng/l). Out of 121 patients with ongoing cholecalciferol supplementation at baseline, 25(OH)D deficiency and insufficiency was observed in 9 (7%) and 16 (13%) patients, respectively, whereas out of 52 patients with no supplementation, 15 (29%) had deficiency and 19 (37%) had insufficiency. Only 85 (26%) patients had optimal 25(OH)D levels (75-100 nmol/l, 30-40 ng/l) at baseline. Seasonal variation was significant for 25(OH)D (p = 0.042) and 1,25(OH)2D (p = 0.001) levels. Living in a rural area was associated with a higher median 25(OH)D concentration as compared with living in an urban area (87 nmol/l, range 16-216 vs 72 nmol/l, range 17-162; p = 0.001). Regular sporting activity was positively associated with 25(OH)D (p = 0.045). Body mass index was inversely related to both 25(OH)D and 1,25(OH)2D (Spearman's rho = -0.24, p <0.001; rho = -0.23, p <0.001, respectively). The levels of 25(OH)D and 1,25(OH)2D were correlated (rho = 0.21, p <0.001). Age and bone mineral density had no significant correlation with the levels of 25(OH)D. Follow-up 25(OH)D was available for 230 patients, 44 (19%) of whom had 25(OH)D deficiency and 47 (21%) had insufficiency; 25 (41.6%) initially 25(OH)D-deficient patients attained sufficient 25(OH)D levels, whereas 33 (16.5%) patients with sufficient baseline 25(OH)D levels became deficient. Only 67 (30%) patients presented optimal 25(OH)D at the follow-up.. A remarkable fraction of the patients had serum 25(OH)D below (40%) or above (30%) optimal levels, and only around 30% of patients had optimal levels. Levels of 25(OH)D and 1,25(OH)2D increased on cholecalciferol supplementation, but the usual supplementation regimens were not adequate to bring 25(OH)D to the optimal range for a large proportion of patients.. EKSG 08/082/2B.

Topics: Breast Neoplasms; Cancer Survivors; Cholecalciferol; Dietary Supplements; Female; Humans; Middle Aged; Surveys and Questionnaires; Switzerland; Vitamin D; Vitamin D Deficiency

Breast cancer ranks second in the list of cancer-related deaths for women. Even under multidisciplinary treatment, 25-50% of patients with breast cancer still ultimately develop metastasis, leading to poor prognosis. In addition to inducing angiogenesis, vascular endothelial growth factor-A (VEGF-A) is believed to directly increase cancer cell metastatic potential and overexpression of VEGF-A is associated with higher invasiveness of breast cancer. 1α,25(OH). Western blot, migration and invasion assays, enzyme-linked immunosorbent assay, and immunofluorescent stain were applied in this study.. VEGF-A increased cell migration and invasion in estrogen receptor-positive (ER+) breast cancer MCF-7 cells. VEGF-A induced an autocrine loop in MCF-7 cells as VEGF-A treatment increased both VEGF-A expression and secretion. The expression of VEGF receptor type 2 (VEGFR2) and neuropilin 1 was also up-regulated by VEGF-A in MCF-7 cells. In addition, F-actin synthesis and LIM domain kinase 1 (LIMK-1) phosphorylation were increased by VEGF-A. VEGF-A also increased β-catenin expression and nuclear translocation of both β-catenin and nuclear factor-ĸB (NF-ĸB), indicating increased β-catenin and NF-ĸB activity. 1α,25(OH)

Topics: Antineoplastic Agents; Blotting, Western; Breast Neoplasms; Cholecalciferol; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Humans; Lim Kinases; MCF-7 Cells; Neoplasm Metastasis; Neuropilin-1; Receptors, Estrogen; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Long-term severe hyperparathyroidism leads to thinning of cortical bone and cystic bone defects referred to as osteitis fibrosa cystica. Cysts filled with hemosiderin deposits may appear colored as "brown tumors." Osteitis fibrosa cystica and brown tumors are occasionally visualized as multiple, potentially corticalis-disrupting bone lesions mimicking metastases by bone scintigraphy or. We report a case of a 72-year-old white woman who presented with malaise, weight loss, and hypercalcemia. She had a history of breast cancer 7 years before. The practitioner, suspecting bone metastases, initiated bone scintigraphy, which showed multiple bone lesions, and referred her to our hospital for further investigations. Laboratory investigations confirmed hypercalcemia but revealed a constellation of primary hyperparathyroidism and not hypercalcemia of malignancy; in the latter condition, a suppressed rather than an increased value of parathyroid hormone would have been expected. A parathyroid adenoma was found and surgically removed. The patient's postoperative course showed a hungry bone syndrome, and brown tumors were suspected. With the background of a previous breast cancer and lytic, partly corticalis-disrupting bone lesions, there was a great concern not to miss a concomitant malignant disease. Biopsies were not diagnostic for either malignancy or brown tumor. Six months after the patient's neck surgery, imaging showed healing of the bone lesions, and bone metastases could be excluded.. This case shows essential differential diagnosis in a patient with hypercalcemia and multiple bone lesions. Whenever multiple, fluorodeoxyglucose-avid bone lesions are found, malignancy and metabolic bone disease should both be included in the differential diagnosis. Fluorodeoxyglucose-avid and corticalis-disrupting lytic lesions also occur in benign bone disease. There may be very few similar cases with heterogeneous and widespread bone lesions reported in the literature, but we think our patient's case is particularly remarkable for its detailed imaging and the well-documented course.

Topics: Aged; Bone Neoplasms; Breast Neoplasms; Calcium; Cholecalciferol; Diagnosis, Differential; Female; Humans; Hypercalcemia; Hyperparathyroidism, Primary; Osteitis Fibrosa Cystica; Parathyroid Neoplasms; Parathyroidectomy; Positron Emission Tomography Computed Tomography; Treatment Outcome; Vitamins

Considerable epidemiological evidence suggests that high levels of circulating vitamin D (VD) are associated with a decreased incidence and increased survival from cancer, i.e., VD may possess anti-cancer properties. The aim of this investigation was therefore to investigate the anti-cancer potential of a low calcaemic vitamin D analogue, i.e., inecalcitol and compare it with the active form of vitamin D, i.e., calcitriol, in a panel of breast cancer cell lines (

Topics: Alkynes; Breast Neoplasms; Calcitriol; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cholecalciferol; Female; Gene Expression Regulation, Neoplastic; Humans; Receptors, Calcitriol; Receptors, Estrogen

Multiple epidemiological studies have shown that high vitamin D

Topics: Antineoplastic Agents; Breast; Breast Neoplasms; Calcitriol; Cell Adhesion; Cell Line, Tumor; Cholecalciferol; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Kallikreins; Ketoconazole; MCF-7 Cells; Membrane Proteins; Neoplasm Recurrence, Local; Peptide Elongation Factors; Ribonucleoprotein, U5 Small Nuclear; Sequence Analysis, RNA; Serpins; Signal Transduction; Transcription, Genetic; Up-Regulation; Vitamin D3 24-Hydroxylase

Metformin is usually used for the treatment of type 2 diabetes. Recently, many studies suggest that metformin and vitamin D have broad-spectrum antitumor activities. Our aim in this research was to study the effects of vitamin D3 combined with metformin on the apoptosis induction and its mechanisms in the human breast cancer cell line MDA-MB-231. Cell proliferation was measured by methylthiazol tetrazolium (MTT) assay. The morphology of cell apoptosis was observed after Hoechst 33342 staining. Here we show that vitamin D3 280 μg/ml or vitamin D3 300 μg/ml or vitamin D3 320 μg/ml seperately combined with metformin 15000 μg/ml exhibited synergistic effects on cell proliferation and apoptosis. The underlying anti-tumor mechanisms may involve m-TOR related pathways, which are related to activating expression of cleaved caspase-3, Bax and p-AMPK, as well as inhibiting expressions of p-Bcl-2, c-Myc, p-IGF-IR, p-mTOR, p-P70S6K, p-S6.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Drug Synergism; Female; Humans; Hypoglycemic Agents; Metformin; Signal Transduction; Tetrazolium Salts; Thiazoles; TOR Serine-Threonine Kinases; Vitamins

With the recent advance in breast cancer therapy, the survival rate of breast cancer patients has improved greatly. In spite of the progress, 25-50% of breast cancer patients eventually will develop metastasis. Due to limited early detection methods, metastasis is usually diagnosed at the late stages beyond recovery likely due to resistance to currently available breast cancer therapies. Thus, a new strategy to prevent cancer cell growth and repress tumor metastasis is desirable. The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], has anti-invasion and anti-migration properties in pre-clinical studies, yet its clinical application has been hampered by its hypercalcemic side effect. Previously, we have demonstrated that a new class of less-calcemic vitamin D analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), is 1000-fold more active than 1α,25(OH)2D3 in suppressing MCF-7 cells growth through cell cycle arrest and apoptosis induction. In the current study, we show for the first time that MART-10 is more active than 1α,25(OH)2D3 in preventing MCF-7 cell invasion and migration likely mediated through the upregulation of E-cadherin, and the downregulation of Snail, Slug, and Twist, the transcription factors implicated in epithelial-mesenchymal transition (EMT), as well as MMP-13. Based on the current in vitro and the highly anti-tumor characteristics of MART-10 in a pancreatic xenograft model, MART-10 is deemed as a promising candidate for breast cancer treatment. Further in vivo animal study comparing MART-10 with 1α,25(OH)2D3 and other potent and less calcemic analogs of vitamin D is warranted.

Topics: Antigens, CD; Antineoplastic Agents; Breast Neoplasms; Cadherins; Cell Movement; Cholecalciferol; Epithelial-Mesenchymal Transition; Female; Gene Expression; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; MCF-7 Cells; Neoplasm Invasiveness; Neoplasm Metastasis; Nuclear Proteins; Snail Family Transcription Factors; Transcription Factors; Twist-Related Protein 1; Vitamin D

Carriers of germline mutations in the BRCA1 gene have a significant increased lifetime risk for being diagnosed with breast cancer. The incomplete penetrance of BRCA1 suggests that environmental and/or genetic factors modify the risk and incidence among mutation carriers. Nutrition and particular micronutrients play a central role in modifying the phenotypic expression of a given genotype by regulating chromatin structure and gene expression. The active form of vitamin D, 1α,25-dihydroxyvitamin D3, is a potent inhibitor of breast cancer growth. Here we report that two non-calcemic analogues of 1α,25-dihydroxyvitamin D3, seocalcitol (EB1089) and QW-1624F2-2, collaborate with BRCA1 in mediating growth inhibition of breast cancer cells and breast cancer stem-like cells. EB1089 induces a G1/S phase growth arrest that coincides with induction of p21waf1 expression only in BRCA1-expressing cells. A complete knockdown of BRCA1 or p21waf1 renders the cells unresponsive to EB1089. Furthermore, we show that in the presence of ligand, BRCA1 associates with vitamin D receptor (VDR) and the complex co-occupies vitamin D responsive elements (VDRE) at the CDKN1A (p21waf1) promoter and enhances acetylation of histone H3 and H4 at these sites. Thus, BRCA1 expression is critical for mediating the biological impact of vitamin D3 in breast tumor cells.

Topics: Acetylation; BRCA1 Protein; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Chromatin Immunoprecipitation; Cyclin-Dependent Kinase Inhibitor p21; Flow Cytometry; Fluorescent Antibody Technique; Histones; Humans; Immunoblotting; Immunoprecipitation; Neoplastic Stem Cells; Promoter Regions, Genetic; Receptors, Calcitriol; Reverse Transcriptase Polymerase Chain Reaction; Transfection

The current strategies for the treatment of breast cancer are essentially based on surgery, preceded and/or followed by chemotherapy often supplemented by radiotherapy and/or the administration of hormonal therapy and monoclonal antibodies. Their combined use has made it possible to increase an overall survival but they are still penalized by adverse effects and toxicity. The marked anti-cancer effects of biological molecule such as somatostatin, melatonin, retinoid, vitamin D3 and prolactin inhibitors have been studied and documented for several decades. Their integrated and synergic action have been demonstrated, but only a few studies have as yet been carried out on their combined application in humans. The aim of the present investigation was to evaluate both the objective clinical response and toxicity of the biological multimodal treatment named Di Bella Method (DBM).. The clinical data from a total of 20 women with a certified diagnosis of breast cancer,defined disease stage, and who independently decided to follow the DBM as first-line treatment, were retrospectively reviewed.. The mean age of the patients was 51 years (min 30; max 73). Twelve (12) patients (60%) presented an early stage disease, while the other 40% had a locally advanced/metastatic stage. An overall clinical benefit was achieved in 75% of cases, with 55% of complete response and 20% of partial response. For metastatic patients, the overall survival rate was 71%. The main toxicity effects included leukopenia, gastrointestinal phenomena and drowsiness.. The preliminary results of this report confirm the positive action of the biological treatment in terms of efficacy and survival, showing a more than favorable profile of tolerability.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cholecalciferol; Cyclophosphamide; Female; Follow-Up Studies; Humans; Melatonin; Middle Aged; Pilot Projects; Retinoids; Retrospective Studies; Somatostatin; Treatment Outcome

Aberrations in DNA methylation patterns have been reported to be involved in driving changes in the expression of numerous genes during carcinogenesis and have become promising targets for chemopreventive action of natural compounds. In the present study, we investigated the effects of all-trans retinoic acid (ATRA), vitamin D₃ and resveratrol alone and in combination with adenosine analogues, 2-chloro-2'-deoxyadenosine (2CdA) and 9-β-d-arabinosyl-2-fluoroadenine (F-ara-A), on the methylation and expression of phosphatase and tensin homologue (PTEN) tumour suppressor gene in MCF-7 and MDA-MB-231 breast cancer cells. The present results showed that in non-invasive MCF-7 cells, ATRA, vitamin D₃ and resveratrol possess high efficacy in the reduction of PTEN promoter methylation. It was associated with PTEN induction as well as DNA methyltransferase down-regulation and p21 up-regulation after treatments with vitamin D₃ and resveratrol, suggesting a complex regulation of the DNA methylation machinery. Vitamin D₃ and resveratrol improved the inhibitory effects of 2CdA and F-ara-A on PTEN methylation in MCF-7 cells; however, only the combined action of vitamin D₃ and 2CdA boosted the induction of PTEN expression, suggesting a cooperation of these compounds in additional processes driving changes in PTEN expression. In contrast, in highly invasive MDA-MB-231 cells, only vitamin D₃ reduced PTEN methylation and induced its expression without notable effects in combined treatments. The present results suggest that natural compounds can find application in epigenetic anticancer therapy aimed at inhibition of promoter methylation of tumour suppressor genes and induction of their expression at early stages of carcinogenesis.

Topics: Adenocarcinoma; Adenosine; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antioxidants; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Cholecalciferol; Cyclin-Dependent Kinase Inhibitor p21; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Neoplasm Proteins; Promoter Regions, Genetic; PTEN Phosphohydrolase; Resveratrol; RNA, Messenger; Stilbenes; Tretinoin; Vitamins

1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3) or calcitriol], the hormonally active vitamin D metabolite, exhibits anticancer actions in models of breast cancer and prostate cancer. Because CYP27B1 (1α-hydroxylase), the enzyme catalyzing 1,25(OH)(2)D(3) formation in the kidney, is also expressed in extrarenal tissues, we hypothesize that dietary vitamin D(3) will be converted to 25(OH)D(3) in the body and then to 1,25(OH)(2)D(3) locally in the cancer microenvironment in which it will exert autocrine/paracrine anticancer actions. Immunocompromised mice bearing MCF-7 breast cancer xenografts showed significant tumor shrinkage (>50%) after ingestion of a vitamin D(3)-supplemented diet (5000 IU/kg) compared with a control diet (1000 IU/kg). Dietary vitamin D(3) inhibition of tumor growth was equivalent to administered calcitriol (0.025, 0.05, or 0.1 μg/mouse, three times a week). Both treatments equivalently inhibited PC-3 prostate cancer xenograft growth but to a lesser extent than the MCF-7 tumors. Calcitriol at 0.05 μg and 0.1 μg caused modest but statistically significant increases in serum calcium levels indicating that the dietary vitamin D(3) comparison was to a maximally safe calcitriol dose. Dietary vitamin D(3) did not increase serum calcium, demonstrating its safety at the concentration tested. The vitamin D(3) diet raised circulating 1,25 dihydroxyvitamin D levels and did not alter CYP27B1 mRNA in the kidney but increased it in the tumors, suggesting that extrarenal sources including the tumors contributed to the elevated circulating 1,25 dihydroxyvitamin D(3). Both calcitriol and dietary vitamin D(3) were equipotent in suppressing estrogen synthesis and signaling and other proinflammatory and growth signaling pathways. These preclinical data demonstrate the potential utility of dietary vitamin D(3) supplementation in cancer prevention and therapy.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; Body Weight; Breast Neoplasms; Calcitriol; Calcium; Cell Line, Tumor; Cholecalciferol; Dietary Supplements; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Ovariectomy; Prostatic Neoplasms; Receptors, Calcitriol; Reverse Transcriptase Polymerase Chain Reaction; Steroid Hydroxylases; Tumor Burden; Vitamin D3 24-Hydroxylase; Vitamins; Xenograft Model Antitumor Assays

In MCF-7 breast tumor cells, ionizing radiation promoted autophagy that was cytoprotective; pharmacological or genetic interference with autophagy induced by radiation resulted in growth suppression and/or cell killing (primarily by apoptosis). The hormonally active form of vitamin D, 1,25D 3, also promoted autophagy in irradiated MCF-7 cells, sensitized the cells to radiation and suppressed the proliferative recovery that occurs after radiation alone. 1,25D 3 enhanced radiosensitivity and promoted autophagy in MCF-7 cells that overexpress Her-2/neu as well as in p53 mutant Hs578t breast tumor cells. In contrast, 1,25D 3 failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell line with low-level expression of the vitamin D receptor. Enhancement of MCF-7 cell sensitivity to radiation by 1,25D 3 was not attenuated by a genetic block to autophagy due largely to the promotion of apoptosis via the collateral suppression of protective autophagy. However, MCF-7 cells were protected from the combination of 1,25D 3 with radiation using a concentration of chloroquine that produced minimal sensitization to radiation alone. The current studies are consistent with the premise that while autophagy mediates a cytoprotective function in irradiated breast tumor cells, promotion of autophagy can also confer radiosensitivity by vitamin D (1,25D 3). As both cytoprotective and cytotoxic autophagy can apparently be expressed in the same experimental system in response to radiation, this type of model could be utilized to distinguish biochemical, molecular and/or functional differences in these dual functions of autophagy.

Topics: Autophagy; Breast Neoplasms; Calcitriol; Cell Line, Tumor; Cholecalciferol; Cytoprotection; Drug Screening Assays, Antitumor; Female; Gene Silencing; Humans; Phagosomes; Radiation Tolerance; Radiation, Ionizing; Receptor, ErbB-2; Transfection; Vacuoles

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Chemotherapy, Adjuvant; Cholecalciferol; Docetaxel; Drug Eruptions; Dysgeusia; Female; Humans; Middle Aged; Stomatitis; Taxoids; Trastuzumab; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

Icb-1 (C1orf38) is a human gene initially described by our group to be involved in differentiation processes of cancer cells. To further elucidate the function of the icb-1 gene in differentiation of breast and endometrial cancer cells, we knocked down its expression by means of shRNA transfection. Knockdown of icb-1 inhibited the vitamin D3-induced up-regulation of E-cadherin expression in both MCF-7 and HEC-1B cells. Induction of E-cadherin expression by all-trans retinoic acid (ATRA) was also blocked in both cell lines expressing icb-1 siRNA. Examination of icb-1 and E-cadherin expression in 66 breast cancer tissue samples revealed a significant positive correlation between the two genes. In MCF-7 cells, silencing of the icb-1 gene inhibited the ATRA- and the vitamin D3-induced up-regulation of lactoferrin and estrogen receptor β expression. The data of our knockdown study suggest that icb-1 may act as a mediator of differentiation signals in breast cancer cells induced by ATRA or vitamin D3. These findings together with the observed co-expression of icb-1 with E-cadherin in breast cancer samples support an important role of the icb-1 gene in cancer cell differentiation.

Topics: Breast Neoplasms; Cadherins; Cell Differentiation; Cell Line, Tumor; Cholecalciferol; Estrogen Receptor beta; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Genital Neoplasms, Female; Humans; Intracellular Signaling Peptides and Proteins; Lactoferrin; Neoplasm Proteins; RNA, Small Interfering; Tretinoin

We designed by docking and synthesized two novel analogues of 1α,25-dihydroxyvitamin D(3) hydroxymethylated at C-26 (2 and 3). The syntheses were carried out by the convergent Wittig-Horner approach via epoxide 12a as a common key intermediate. The antiproliferative and transactivation potency of the compounds was evaluated in colon and breast cancer cell lines. The analogues showed a similar but reduced activity compared to 1,25(OH)(2)D(3). Analogue 3 was more potent than analogue 2, and in some assays it exhibited potency similar to that of the natural ligand.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Chlorocebus aethiops; Cholecalciferol; Colonic Neoplasms; COS Cells; Drug Design; Female; Humans; Ligands; Protein Binding; Receptors, Calcitriol

DNA methylation is considered as a potential cause of aberrations in regulation of gene expression during carcinogenesis. Therefore, changes in DNA methylation patterns may be targets for chemoprevention. In the present study, we investigated effects of all-trans retinoic acid (ATRA), vitamin D(3), and resveratrol alone and in combination with adenosine analogues: 2-chloro-2'-deoxyadenosine (2CdA) and 9-beta-D-arabinosyl-2-fluoroadenine (F-ara-A), on methylation and expression of retinoic acid receptor beta 2 (RAR beta 2) in MCF-7 and MDA-MB-231 breast cancer cell lines. Alterations in methylation and expression levels after treatment of cells with the tested compounds were evaluated by methylation-sensitive restriction analysis (MSRA) and real-time PCR, respectively. RAR beta 2 promoter in the tested fragment was partially methylated in MCF-7 cells and non-methylated in MDA-MB-231 cells. In MCF-7 cells, all compounds, except for resveratrol, inhibited promoter methylation and increased expression of RAR beta 2. All natural compounds improved the action of 2CdA and F-ara-A on RAR beta 2 methylation and/or expression. Combination of ATRA or vitamin D(3) with 2CdA was the most effective. In MDA-MB-231 cells, only 2CdA, F-ara-A, and ATRA induced RAR beta 2 expression without any notable effects in combined treatment. Our results demonstrate that both natural compounds and adenosine analogues are able to reduce promoter methylation and/or induce expression of RAR beta 2 in non-invasive MCF-7 cells. Furthermore, the natural compounds improve effects of adenosine analogues, however only at early non-invasive stages of carcinogenesis.

Topics: Adenosine; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cholecalciferol; Cladribine; DNA Methylation; Drug Screening Assays, Antitumor; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Promoter Regions, Genetic; Receptors, Retinoic Acid; Resveratrol; Stilbenes; Transcriptional Activation; Tretinoin; Vidarabine

We have synthesized several isomers of 19-nor-vitamin D analogues possessing a hydroxy group at C-2 as well as novel derivatives bearing an epoxy substituent at the A-ring. All vitamins were prepared in convergent syntheses utilizing the modified Julia olefination. 1alpha,2alpha,25-Trihydroxy-19-nor-vitamin D(3) (3) and 2beta,3beta-epoxy-1alpha,25-dihydroxy-3-deoxy-19-nor-vitamin D(3) (10), which showed the highest affinity to the vitamin D receptor, displayed the highest potency among the tested compounds to inhibit the proliferation of MCF-7 breast cancer cells.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Female; Humans; Molecular Conformation; Receptors, Calcitriol; Structure-Activity Relationship

Topics: Breast Neoplasms; Cholecalciferol; Female; Humans; Vitamin D; Vitamin D Deficiency

1alpha,25-dihydroxyvitamin D3 and its analogue, Seocalcitol (EB1089), are able to reverse or slow the process of carcinogenesis in experimental models and cell cultures. The aim of this study was to investigate the effect of administration vitamin D or Seocalcitol to female Sprague-Dawley rats with 1-methyl-1-nitrosourea (MNU)-induced carcinogenesis of mammary glands on binding characteristics and mRNA levels of thyroid hormone receptors (TRs). Chemopreventive administration of vitamin D caused significant reduction of animal body weight. The expression of TRalpha mRNA was significantly higher in liver of animals treated with vitamin D after detection of first tumour. In our experiment, administration of vitamin D or Seocalcitol significantly reduced KA (group MNU+Seo; MNU+D) and increased Bmax (group MNU+Seo) of thyroid receptors in liver when compared to healthy animals. We show that the activity type I 5'-deiodinase was significantly decreased in livers of animals treated with vitamin D. The data from our in vivo experiment has clearly shown, for the first time, that vitamin D but not Seocalcitol i) may affect the body weight of animals, ii) can cause an increase in the expression of TRalpha in rat liver, remaining the functionality of the TRs unaffected, and iii) is responsible for type I iodothyronine 5'-deiodinase activity decrease in rat liver, remaining the expression of the enzyme unaffected.

Topics: Animals; Body Weight; Breast Neoplasms; Calcitriol; Cholecalciferol; DNA; Female; Gene Expression Regulation; Iodide Peroxidase; Liver; Methylnitrosourea; Organ Size; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroid Hormone Receptors alpha

Analogs of 1,25-dihydroxyvitamin D3 with a reversed configuration at C-1 or C-24 and E or Z geometry of the double bond at C-22 in the side chain or at C-5 in the triene system were examined for their antiproliferative activity in vitro against a spectrum of various human cancer cell lines. The analogs coded PRI-2201 (calcipotriol), PRI-2202 and PRI-2205, such as calcitriol and tacalcitol (used as a referential agents), revealed antiproliferative activity against human HL-60, HL-60/MX2, MCF-7, T47D, SCC-25 and mouse WEHI-3 cancer cell lines. The toxicity studies in vivo showed that PRI-2202 and PRI-2205 are less toxic than referential agents. Even at total doses of 2.5-5.0 mg/kg distributed during 5 successive days, no changes in body weight were observed. Calcitriol and tacalcitol showed toxicity in the same protocol at 100 times lower doses. Calcipotriol was lethal to all mice after administration of a total dose of 5.0 mg/kg. The analog PRI-2205 appeared to be more active in mouse Levis lung cancer tumor growth inhibition than calcitriol, calcipotriol or PRI-2202. This analog did not reveal calcemic activity at doses which inhibit tumor growth in vivo nor at higher doses.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Calcitriol; Calcium; Carcinoma, Lewis Lung; CD11b Antigen; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Coloring Agents; Female; Fibroblasts; HL-60 Cells; Humans; Lipopolysaccharide Receptors; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Pancreatic Neoplasms; Prostatic Neoplasms; Rhodamines; Stereoisomerism; Tetrazolium Salts; Thiazoles

Active metabolites of vitamin A and D are well known to act as growth inhibitors in hormone-related prostate and breast cancers. When various concentrations of 1alpha,25-dihydroxyvitamin D3 (vitamin D3), all-trans-retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA) were examined, the androgen-stimulated growth of mouse mammary carcinoma SC-3 cells was inhibited by vitamin D3 alone in a dose-dependent manner. A flow cytometer analysis showed that vitamin D3 leads SC-3 cells to relative G1-growth arrest after 72 h. Characterization of vitamin D3-responsive genes using an oligonucleotide microarray demonstrated that 220 genes were upregulated at more than threefold, and 84 genes were downregulated to less than one-third, compared with the testosterone-stimulated SC-3 cells. Neither cyclin-dependent kinase inhibitors (CDKIs) nor the antiapoptotic bcl-2 gene were induced in vitamin D3-responsive genes, with the exception of a slight induction of p15(INK4B). Importantly, fgf8 was markedly repressed in response to vitamin D3. The exogenous addition of FGF8 canceled the growth suppression by vitamin D3 in SC-3 cells, suggesting that the repression of fgf8 is an indispensable step in vitamin D3-mediated growth inhibition. In reporter assays using the ARE-containing artificial construct and the natural androgen-regulated PSA promoter, co-transfection of the vitamin D receptor (VDR) and androgen receptor (AR) suppressed AR-stimulated promoter activity. In addition, vitamin D3 also suppressed androgen-stimulated promoter activity in the stably transfected SC-3 cells. Moreover, VDR repressed the core promoter activity of fgf8 in COS1 cells and in the SC-3 cells. All these findings strongly suggest that vitamin D3 serves as a negative regulator for both androgen-related and fgf8 transcriptions.

Topics: Androgens; Animals; Breast Neoplasms; Cell Line; Cell Proliferation; Chlorocebus aethiops; Cholecalciferol; Down-Regulation; Fibroblast Growth Factor 8; Gene Expression Regulation, Neoplastic; Mammary Glands, Animal; Mice; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; Transcription, Genetic; Tretinoin

We hypothesized that deregulated corepressor actions, with associated histone deacetylation activity, epigenetically suppressed vitamin D receptor (VDR) responsiveness and drives resistance towards 1alpha,25-dihydroxyvitamin D(3).. Profiling, transcriptional, and proliferation assays were undertaken in 1alpha,25(OH)(2)D(3)-sensitive MCF-12A nonmalignant breast epithelial cells, a panel of breast cancer cell lines, and a cohort of primary breast cancer tumors (n = 21).. Elevated NCoR1 mRNA levels correlated with suppressed regulation of VDR target genes and the ability of cells to undergo arrest in G(1) of the cell cycle. A similar increased ratio of corepressor mRNA to VDR occurred in matched primary tumor and normal cells, noticeably in estrogen receptor alpha-negative (n = 7) tumors. 1alpha,25(OH)(2)D(3) resistance in cancer cell lines was targeted by cotreatments with either 1alpha,25(OH)(2)D(3) or a metabolically stable analogue (RO-26-2198) in combination with either trichostatin A (TSA; histone deacetylation inhibitor) or 5-aza-2'-deoxycytidine (DNA methyltransferase inhibitor). Combinations of vitamin D(3) compounds with TSA restored VDR antiproliferative signaling (target gene regulation, cell cycle arrest, and antiproliferative effects in liquid culture) to levels which were indistinguishable from MCF-12A cells.. Increased NCoR1 mRNA is a novel molecular lesion in breast cancer cells, which acts to suppress responsiveness of VDR target genes, resulting in 1alpha,25(OH)(2)D(3) resistance and seems to be particularly associated with estrogen receptor negativity. This lesion provides a novel molecular diagnostic and can be targeted by combinations of vitamin D(3) compounds and low doses of TSA.

Topics: Azacitidine; Breast Neoplasms; Calcitriol; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Decitabine; Female; Humans; Hydroxamic Acids; Nuclear Proteins; Nuclear Receptor Co-Repressor 1; Receptors, Calcitriol; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Structure-Activity Relationship; Time Factors; Tumor Cells, Cultured

Although both the antiapoptotic function of survivin and vitamin D3 (VD3)-mediated cell growth inhibition and apoptosis have been extensively studied, it is not known whether survivin plays a role in VD3 compound-mediated cell growth inhibition and apoptosis induction. Using an isogenic model of MCF-7 breast adenocarcinoma cells (MCF-7E and MCF-7L sublines that are sensitive and resistant to VD3 compounds), we found that VD3 compounds effectively downregulated survivin in VD3-sensitive MCF-7E cells, which was associated with VD3-induced apoptosis. In contrast, VD3 compounds failed to downregulate survivin in VD3-resistant MCF-7L cells, which showed resistant to VD3-induced apoptosis. However, inhibition of survivin expression by small interfering RNA (siRNA) induced cell death per se and further sensitized VD3-induced apoptosis in MCF-7L cells, indicating that the inability of these cells to respond to VD3 is due to the failure to downregulate survivin. Forced expression of survivin not only blocked VD3-mediated G1 cell accumulation but also increased S and G2/M cell populations. VD3 treatment rapidly triggered the activation of p38 MAPK signaling in MCF-7E cells but not in MCF-7L cells. Moreover, inhibition of p38 activation diminished VD3-mediated survivin inhibition and partially rescued VD3-induced cell death. We further showed that VD3 increased the expression of TGF(beta)1 and TGF(beta) receptor 2, and that blocking the function of TGF(beta) receptor 2 diminished VD3 compound-mediated survivin downregulation. Thus, we propose that the VD3 compound-induced growth inhibition and apoptosis induction are at least partially dependent on survivin downregulation via VD3-induced TGFbeta signaling and the activation of p38 MAPK pathway. Targeting survivin through these pathways may lead to novel applications for cancer therapeutics.

Topics: Adenocarcinoma; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cholecalciferol; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Neoplasm Proteins; p38 Mitogen-Activated Protein Kinases; Phosphorylation; RNA, Small Interfering; Survivin; Transforming Growth Factor beta

The S14 (spot 14) gene encodes a protein that is predominantly expressed in lipogenic tissues, such as the liver, white and brown adipose tissues and the lactating mammary glands. Accumulated evidence suggests that S14 could play an important role in the induction of lipogenic enzymes. In humans, the S14 locus resides in the chromosome region 11q13, which is frequently amplified in breast tumours, and as a result, it has been suggested that this protein could play a role in the metabolism and growth of these kinds of tumours. In the present study, we have examined the effects of S14 overexpression in MCF-7 human breast cancer cells. We found that S14 causes (i) an inhibition of cell proliferation and of anchorage-independent growth, (ii) a marked reduction in the number of viable cells and (iii) the induction of differentiation and cell death of these cells. The inhibition of cell growth was associated with a decrease in the expression of cyclin D1 and a reduction of cyclin D1 promoter activity. Increased expression of S14 also caused the accumulation of cytochrome c in the cytosol and loss of mitochondrial membrane potential. These findings suggest that S14 may function as an important modulator of tumorigenesis in human breast by decreasing cell growth and inducing cell death and differentiation.

Topics: Breast Neoplasms; Cell Death; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Cyclin D1; Gene Expression; Humans; Nuclear Proteins; Promoter Regions, Genetic; Prostaglandin D2; Proteins; Time Factors; Transcription Factors; Tretinoin

Urokinase plasminogen activator (uPA), its cell-bound receptor (uPAR) and its main inhibitor plasminogen activator type 1 (PAI-1) are present primarily in stromal cells in invasive breast carcinoma. The purpose of this study was to investigate the regulation by 1,25 dihydroxyvitamin-D3 (VD3) of these invasion-associated markers expressed in breast cancer tumors under organ culture, which preserves the interacting network of tumor and stromal cells. Breast carcinoma slices (30 cases), obtained using the Krumdieck tissue slicer, cultured for 48 h in the presence or absence of 100 nM vitamin D3, were embedded in formalin-fixed paraffin. uPA, uPAR, PAI-1 and VD3 receptor (VDR) were analyzed by immunohistochemistry, and their expression, detected in tumor cells and fibroblasts of the specimens, was not statistically changed by culture conditions. The proportion of cases expressing uPA, uPAR and PAI-1 was not affected by VD3 in epithelial cells, but the fraction of cases displaying strong PAI-1 reactivity in fibroblasts was reduced ( P=0.016) compared with control slices. Fibroblasts isolated from invasive ductal carcinomas and from normal breast tissues expressed higher VDR mRNA levels than epithelial cells. In cultured tumor fibroblasts, PAI-1 immunostaining and mRNA levels were reduced by VD3-limiting fibroblast contribution to invasion.

Topics: Blotting, Northern; Breast Neoplasms; Carcinoma, Ductal; Cell Line, Tumor; Cholecalciferol; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Organ Culture Techniques; Plasminogen Activator Inhibitor 1; Receptors, Calcitriol; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; RNA, Messenger; Urokinase-Type Plasminogen Activator

To investigate whether prognosis of breast-, colon- and prostate cancer may be related to vitamin D(3), induced from solar ultra-violet (UV) radiation, through studies on geographical and seasonal variations in UV radiation.. This study includes 115,096 cases of breast-, colon- or prostate cancer, diagnosed between 1964 and 1992. Among these, 45,667 deaths due to the cancer were registered. On the basis of a north-south gradient in solar UV radiation and geographical climatic differences, Norway was divided into eight residential regions. According to seasonal variations in UV radiation, four periods of diagnosis during the year were used. Case fatality according to residential region and to season of diagnosis was estimated using Cox regression. The effects of occupational sun exposure, childbearing pattern and educational level were also evaluated.. No geographic variation in case fatality was observed for the three cancer types studied. A significant variation in prognosis by season of diagnosis was observed. Diagnoses during summer and fall, the seasons with the highest level of vitamin D(3), revealed the lowest risk of cancer death.. The results suggest that a high level of vitamin D(3) at the time of diagnosis, and thus, during cancer treatment, may improve prognosis of the three cancer types studied.

Topics: Breast Neoplasms; Cholecalciferol; Colonic Neoplasms; Educational Status; Female; Humans; Male; Norway; Occupational Exposure; Prognosis; Prostatic Neoplasms; Risk Factors; Seasons; Sunlight; Treatment Outcome

Previous work from this laboratory has demonstrated that the vitamin D(3) analogs EB 1089 and ILX 23-7553 enhance the response of breast tumor cells to ionizing radiation and promote radiation-induced apoptotic cell death. The current studies were designed to more closely simulate clinical radiotherapy in the treatment of breast cancer by examining the utility of ILX 23-7553 as an adjunct to fractionated ionizing radiation. The potential toxicity to normal tissue of the combination of ILX 23-7553 and fractionated radiation was assessed in a model of BJ human fibroblasts in culture.. MCF-7 cells and human fibroblasts were treated with fractionated radiation alone (5x2 Gy over 3 days), ILX 23-7553 alone (50 n M) or ILX 23-7553 followed by 5x2 Gy. Viable cell numbers were determined by trypan blue exclusion and apoptosis by the TUNEL assay. A statistical model of additivity was utilized to assess the nature of the interaction between ILX 23-7553 and fractionated radiation.. Radiation and ILX 23-7553 each alone reduced viable cell numbers by 72+/-3.1% and 62+/-4.8%, respectively. Pretreatment with ILX 23-7553 followed by 5x2 Gy reduced viable cell numbers by 93.2+/-0.7%. The interaction between ILX 23-7553 and fractionated radiation appeared to be additive despite the fact that the combination of ILX 23-7553 and fractionated radiation also promoted a twofold increase in apoptotic cell death. ILX 23-7553 failed to enhance the response to radiation or to promote apoptosis in BJ human foreskin fibroblasts.. ILX 23-7553 enhanced the antiproliferative and apoptotic effects of fractionated ionizing radiation in MCF-7 breast cancer cells. These effects appeared to be selective in that similar responses were not observed in a model of normal human fibroblasts. Vitamin D(3) analogs such as ILX 23-7553 may prove to have utility in combination with conventional radiotherapy of breast cancer as well as other malignancies which are sensitive to vitamin D(3).

Topics: Apoptosis; Breast Neoplasms; Cholecalciferol; Female; Fibroblasts; Humans; Radiation-Sensitizing Agents; Radiotherapy; Tumor Cells, Cultured

In estrogen receptor (ER) positive breast cancer cells such as MCF-7 cells, the anti-tumor effects of 1,25(OH)(2)D(3) (1,25D(3)) may be secondary to disruption of estrogen mediated survival signals. If so, then sensitivity to 1,25D(3) mediated growth arrest could be reduced in estrogen independent breast cancer cells. The aim of these studies was to determine the effects of 1,25D(3) and EB1089 on the ER negative, invasive human breast cancer cell line SUM-159PT. 1,25D(3) and EB1089 reduced SUM-159PT cell growth subsequent to elevation of p27 and p21 levels. 1,25D(3) mediated apoptosis of SUM-159PT cells was associated with an enrichment of membrane bound bax, a redistribution of cytochome c from the mitochondria to the cytosol and PARP cleavage. 1,25D(3) and EB1089 also inhibited SUM-159PT cell invasion through an 8 microM Matrigel membrane. In pre-clinical studies, EB1089 dramatically reduced the growth of SUM-159PT xenografts in nude mice. The decreased size of tumors from EB1089 treated mice was associated with decreased proliferation and increased DNA fragmentation. Our data support the concept that Vitamin D(3) compounds trigger apoptosis by mechanisms independent of estrogen signaling. These studies indicate that Vitamin D(3) based therapeutics may be beneficial, alone or in conjunction with other agents, for the treatment of estrogen independent breast cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biocompatible Materials; Blotting, Western; Breast Neoplasms; Calcitriol; Cell Division; Cholecalciferol; Collagen; Cytosol; Dose-Response Relationship, Drug; Drug Combinations; Electrophoresis, Polyacrylamide Gel; Estrogen Receptor alpha; Estrogens; Humans; Laminin; Ligands; Mice; Mice, Nude; Mitochondria; Neoplasm Invasiveness; Neoplasm Transplantation; Poly(ADP-ribose) Polymerases; Protein Binding; Proteoglycans; Receptors, Calcitriol; Receptors, Estrogen; Subcellular Fractions; Time Factors; Tumor Cells, Cultured; Vitamin D

Evidence has accumulated that 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] is involved in the regulation of the proliferation of breast tumor cells. For complete tumor suppression high hypercalcemic doses of 1,25-(OH)(2)D(3) are needed. The aim of this study was to assess the effect of combined treatment of 1,25-(OH)(2)D(3) at low doses and melatonin (MEL) on the proliferation of estrogen-responsive rat breast cancer cell line RM4.. RM4 cell proliferation was assessed by [3H]thymidine uptake. The presence of TGF-beta(1) in serum-free conditioned medium was determined by inhibition antibody binding assay.. In 17-betaE cultured RM4 cells both MEL and 1,25-(OH)(2)D(3) alone and in combination significantly reduced [3H]thymidine incorporation in a dose-related fashion. MEL by itself was ineffective in inhibiting the FCS-cultured RM4 cells, while 1,25-(OH)(2)D(3) strongly inhibited [3H]thymidine incorporation. Meanwhile, MEL increased the sensitivity of the FCS-cultured RM4 cells to 1,25-(OH)(2)D(3) in the combined regimen, from 20- to 100-fold. MEL significantly enhanced the TGF-beta(1) secretion from RM4 cells and vitamin D(3) increased the TGF-beta(1) secretion in a dose-dependent manner, from 2- to 7-fold. Moreover, a further enhancement of the TGF-beta(1) release was obtained with the combined treatment, but only for low 1,25-(OH)(2)D(3) concentrations. The addition of monoclonal anti-TGF-beta(1) antibody to the medium of RM4 cells exposed to vitamin D(3) alone or in combination with MEL increased the [3H]thymidine uptake compared to the correspondent cells cultured without antibody.. Our data point to a potential benefit of combination therapy with 1,25-(OH)(2)D(3) and MEL in the treatment of breast cancer and suggest that the growth inhibition could be related, at least in part, to the enhanced TGF-beta(1) secretion.

Topics: Adjuvants, Immunologic; Animals; Breast Neoplasms; Cell Division; Cholecalciferol; Female; Growth Inhibitors; Melatonin; Rats; Receptors, Estrogen; Transforming Growth Factor beta; Tumor Cells, Cultured

Breast and prostate cancer are leading causes of cancer death in the Western world. Hormone ablation is the primary therapy for invasive disease, but the tumour often recurs in an androgen or oestrogen receptor negative form for which novel therapies are sought urgently. The vitamin D receptor (VDR) may provide an important alternative therapeutic target. However, cancer cell line models from these tissues display a range of sensitivities to the antiproliferative effects of 1alpha,25dihydroxyvitamin D3 (1alpha,25(OH)2D3). The reason for apparent 1alpha,25(OH)2D3 insensitivity is currently unknown and we have investigated epigenetic mechanisms that may suppress the transcriptional activity of the VDR. Nuclear co-repressors have associated histone deacetylase (HDAC) activity, which keeps chromatin in a closed, transcriptionally silent state. We have found that the aggressive cancer cell lines with relative insensitivity to 1alpha,25(OH)2D3 have elevated nuclear co-repressor levels. For example, PC-3 prostate cancer cells have a significant 1.8-fold elevation in the co-repressor SMRT compared to normal epithelial cells (P < 0.05). We believe that a combination of elevated co-repressor level with reduced VDR content can cause 1alpha,25(OH)2D3 resistance. Consistent with this, we have shown that combining a low dose of HDAC inhibitor Trichostatin A (15 nM TSA) with 1alpha,25(OH)2D3 (100 nM) synergistically inhibits the proliferation of PC-3 prostate and MDA-MB-231 breast cancer cell lines. The inhibition of proliferation was potentiated further by treating cells with 19-nor-hexafluoride vitamin D3 analogues instead of 1alpha,25(OH)2D3, plus TSA. For example, the combination of 1alpha,25(OH)2D3 and TSA-inhibited MDA-MB-231 cell proliferation by 38% (+/-5%), whereas Ro26-2198 (1alpha,25-(OH)2-16,23Z-diene-26,27-F6-19-nor-D3) and TSA inhibited growth by 62% (+/-2%). Therapeutically the hypercalcaemic side effects associated with 1alpha,25(OH)2D3 could be minimized by combining low doses of potent 1a,25(OH)2D3 analogues with HDAC inhibitors as a novel anticancer regime for hormone-insensitive prostate and breast cancer.

Topics: Androgens; Antineoplastic Agents; Breast Neoplasms; Cell Division; Cholecalciferol; DNA-Binding Proteins; Drug Synergism; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Ligands; Male; Neoplasms, Hormone-Dependent; Nuclear Receptor Co-Repressor 2; Prostatic Neoplasms; Repressor Proteins; Tumor Cells, Cultured; Vitamin D

The signaling connection between mitogen-activated protein kinases(MAPKs) and nuclear steroid receptors is complex and remains mostly unexplored. Here we report that stress-activated protein kinases p38 and JNK trans-activate nuclear steroid vitamin D receptor (VDR) gene and increase vitamin D(3)-dependent growth inhibition in human breast cancer cells. Activation of p38 and JNK by an active MAPK kinase 6 stimulates VDR promoter activity independently of the ligand vitamin D(3) and estrogen receptor expression. Moreover, stimulation of the endogenous stress pathways by adenovirus-mediated delivery of recombinant MAPK kinase 6 also activates VDR and sensitizes MCF-7 cells to vitamin D(3)-dependent growth inhibition. Both the p38 and JNK MAPK pathways and the downstream transcription factor c-Jun/AP-1 are required for the VDR stimulation, as revealed by application of their dominant negatives, the specific p38 inhibitor SB203580, and site-directed mutagenesis of the AP-1 element in the VDR promoter. The essential role of the p38 and JNK stress pathways in up-regulation of VDR expression is further confirmed by using the chemical stimulator arsenite. These results establish a signaling connection between the stress MAPK pathways and steroid hormone receptor VDR expression and thereby offer new insights into regulation of cell growth by the MAPK pathways through regulation of vitamin D(3)/VDR activity.

Topics: Breast Neoplasms; Calcium-Calmodulin-Dependent Protein Kinases; Cell Division; Cholecalciferol; Female; Humans; Imidazoles; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 6; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Pyridines; Receptors, Calcitriol; Transcription Factor AP-1; Transcriptional Activation; Tumor Cells, Cultured

Melatonin inhibits proliferation of the estrogen-responsive MCF-7 human breast cancer cells. The objective of this work was to assess whether melatonin not only regulates MCF-7 cell proliferation but also induces apoptosis. In this experiment we used 1,25-dihydroxycholecalciferol (D3) as a positive control because it inhibits MCF-7 cell proliferation and induces apoptosis. MCF-7 cells were cultured with either I nM melatonin, 100 nM D3 or its diluent to determine their effects on cell proliferation, cell viability, cell-cycle phase distribution, population of apoptotic cells, and expression of p53, p21WAF1, bcl-2, bcl-X(L) and bax proteins. After 24 or 48 hr of incubation, both melatonin and D3-treatment significantly decreased the number of viable cells in relation to the controls, although no differences in cell viability were observed between the treatments. The incidence of apoptosis, measured as the population of cells falling in the sub-G1 region of the DNA histogram, or by the TUNEL reaction, was similar in melatonin-treated and control cells whereas, as expected, apoptosis was higher among cells treated with D3 than in controls. The expression of p53 and p21WAF1 proteins significantly increased after 24 or 48 hr of incubation with either melatonin or D3. No significant changes in bcl-2, bcl-XL and bax mRNAs were detected after treatment with melatonin whereas in D3-treated cells, a significant drop in bcl-XL was observed. These data support the hypothesis that melatonin reduces MCF-7 cell proliferation by modulating cell-cycle length through the control of the p53-p21 pathway, but without clearly inducing apoptosis.

Topics: Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Breast Neoplasms; Cell Cycle; Cell Division; Cholecalciferol; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Female; Gene Expression Regulation, Neoplastic; Humans; Melatonin; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured; Tumor Suppressor Protein p53

1alpha,25-Dihydroxyvitamin D(3) [1,25(OH)2D3] inhibits growth of cells derived from a variety of tumors in vitro and in vivo. Proliferation in vitro of human SCC25 cells, derived from a primary squamous cell carcinoma (SCC) of the tongue, was blocked by 1,25(OH)2D3 and its analog EB1089. A similar effect was observed with 13-cis retinoic acid (RA), which has been used in chemoprevention of SCC. We identified amphiregulin, a member of the epidermal growth factor family, as a 1,25(OH)2D3 target gene in SCC25 cells. Induction of amphiregulin mRNA by 1,25(OH)2D3 was rapid and sustained over 48 h, and was unaffected by cycloheximide. 1,25(OH)2D3 also induced amphiregulin mRNA in estrogen receptor-positive and -negative human breast cancer cell lines, but not in LNCaP human prostate cancer cells. RAR- or RXR-specific retinoids did not affect amphiregulin mRNA levels in SCC25 cells; however, 13-cis RA partially blocked the response to 1,25(OH)2D3. Amphiregulin partially inhibited growth of SCC25 cells in culture. Our data show that amphiregulin is a 1,25(OH)2D3 target gene, and suggest that its induction may contribute to the growth inhibitory effects of 1,25(OH)2D3.

Topics: Amphiregulin; Antineoplastic Agents; Breast Neoplasms; Calcitriol; Carcinoma, Squamous Cell; Cell Division; Cholecalciferol; Dose-Response Relationship, Drug; EGF Family of Proteins; Gene Expression Regulation, Neoplastic; Glycoproteins; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Isotretinoin; RNA, Messenger; Tumor Cells, Cultured

This study provides a detailed and exact evaluation of the interactions between vitamin D3 receptor (VDR), retinoid X receptor (RXR), and vitamin D3 responsive elements (VDREs) mediated by two novel 14-epianalogs of 1,25-dihydroxyvitamin D [1,25(OH)2D3], 19-nor-14-epi-23-yne-1,25(OH)2D3 (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25(OH)2D3 (TX 527). Both analogs were more potent (14- and 75-fold, respectively) than 1,25(OH)2D3 in inhibiting cell proliferation and inducing cell differentiation. However, DNA-independent experiments indicated that both analogs had a lower affinity to VDR and that the stability of the induced VDR conformation, as measured by limited protease digestion assays, was similar (TX 527) or even weaker (TX 522) than that induced by the parent compound. However, DNA-dependent assays such as gel shift experiments revealed that those analogs were slightly more potent (3-7 times) than 1,25(OH)2D3 in enhancing binding of VDR-RXR heterodimers to a direct repeat spaced by three nucleotides (DR3) type VDRE. The functional consequences of the ligand-VDR-RXR-VDRE interactions observed in vitro were subsequently evaluated in transfection experiments. Both 14-epianalogs enhanced transcription of VDRE containing reporter constructs more efficiently than 1,25(OH)2D3 in COS-1 and MCF-7 cells regardless of the presence of ketoconazole. Transactivation activity is suggested to be a cell-specific process because maximal transcriptional induction and the half-maximal transactivation concentration for each reporter construct were different in both cell lines. The superagonistic transactivation activity closely resembled the biological potency of these analogs on the inhibition of MCF-7 cell proliferation. These data clearly indicate that superagonistic activity starts beyond the binding of the ligand-heterodimer (VDR-RXR) complex to VDRE and thus probably involves coactivator/corepressor molecules.

Topics: Adenocarcinoma; Alkynes; Animals; Breast Neoplasms; Calcitriol; Cell Division; Chlorocebus aethiops; Cholecalciferol; COS Cells; Dimerization; DNA; Dose-Response Relationship, Drug; Gene Expression Regulation; Humans; Ketoconazole; Macromolecular Substances; Mice; Protein Conformation; Protein Multimerization; Receptors, Calcitriol; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors; Transcriptional Activation; Transfection; Tumor Cells, Cultured

Ionizing radiation and the anthracycline antibiotic, Adriamycin, generally fail to promote a primary apoptotic response in experimental breast tumor cell lines. Similarly, the primary response of breast tumor cells to vitamin D3 (1,25(OH)2D3) and vitamin D3 analogs such as EB 1089 is growth inhibition. Previous studies have demonstrated that pretreatment of MCF-7 breast tumor cells with vitamin D3 or EB 1089 can increase sensitivity to both Adriamycin and irradiation.. The capacity of the vitamin D3 analog, ILX 23-7553, to enhance the antiproliferative and cytotoxic effects of Adriamycin or irradiation and to promote apoptosis in MCF-7 breast tumor cells was assessed in the present study.. Pretreatment of MCF-7 cells with ILX 23-7553 followed by Adriamycin or irradiation decreased viable cell numbers by 97% and 93%, respectively. Cell numbers were reduced by 56%, 74% and 75% by ILX 23-7553, Adriamycin and irradiation alone. Pretreatment with ILX 23-7553 also shifted the dose response curve for clonogenic survival, increasing sensitivity to Adriamycin 2.5-fold and sensitivity to radiation fourfold. In addition, ILX 23-7553 pretreatment conferred sensitivity to Adriamycin- or irradiation-induced DNA fragmentation and resulted in morphological changes indicative of apoptotic cell death in MCF-7 cells. Statistical analysis demonstrated that ILX 23-7553 interacts additively and not synergistically with both Adriamycin and irradiation.. ILX 23-7553 enhances the effects of Adriamycin and irradiation in MCF-7 breast tumor cells by decreasing viable cell numbers, reducing clonogenic survival and inducing apoptotic cell death. Current studies are focused on elucidating the mechanisms underlying the induction of apoptosis as well as understanding the nature of the interactions between ILX 23-7553 and Adriamycin or irradiation.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cholecalciferol; Doxorubicin; Drug Synergism; Female; Humans; Tumor Cells, Cultured

In this study, we address whether TGFbeta signaling mediates vitamin D3 analog-induced growth inhibition in nonmalignant and malignant breast cells. Normal mammary epithelial cells (184), immortalized nonmalignant mammary epithelial cells (184A1 and MCF10A), and breast cancer cells (early passage MCF7: MCF7E) were sensitive to the inhibitory effects of vitamin D3 analogs (EB1089 and MC1288) while late passage MCF7 breast cancer (MCF7L) cells were relatively resistant. A similar pattern of sensitivity to TGFbeta was observed with these cells. Thus, the sensitivity to the vitamin D3 analogs correlated with the sensitivity to TGFbeta. MCF7L TGFbetaRII-transfected cells, which have autocrine TGFbeta activity, were more sensitive to EB1089 than MCF7L cells. TGFbeta neutralizing antibody was found to block the inhibitory effects of these analogs. These results are consistent with the idea that autocrine TGFbeta signaling mediates the anti-proliferative effects of the vitamin D3 analogs in these cells. The expression of TGFbeta isoforms and/or TGFbeta receptors was induced by the analogs in the vitamin D3 and TGFbeta sensitive cells. Vitamin D3 analogs did not induce TGFbeta or TGFbeta receptor expression in the resistant MCF7L cells. Therefore, EB1089 induces autocrine TGFbeta activity through increasing expression of TGFbeta isoforms and/or TGFbeta receptors. In addition, EB1089 induced nuclear VDR protein levels in the sensitive 184A1 cells but not in the resistant MCF7L cells. 184A1 cells were more sensitive to EB1089-induced VDR-dependent transactivation than MCF7L cells as measured by a luciferase reporter construct containing the VDRE, indicating a defect of VDR signaling in MCF7L cells. Smad3, a TGFbeta signaling mediator, coactivated VDR-dependent transactivation in 184A1 cells but not in MCF7L cells. These results indicate that Smad3 coactivates VDR to further enhance TGFbeta signaling and vitamin D3 signaling in the sensitive 184A1 cells. The results also indicate that Smad3 is not of itself sufficient to coactivate VDR in TGFbeta/vitamin D3 resistant MCF7L cells and other factors are required. We found that the PI 3-kinase pathway inhibitor LY29004 inhibited the synergy of TGFbeta and EB1089 on VDR-dependent transactivation activity. This indicates that the crosstalk between TGFbeta and vitamin D signaling is also PI 3-kinase pathway dependent.

Topics: Activin Receptors, Type I; Antibodies, Blocking; Antineoplastic Agents; Autocrine Communication; Breast; Breast Neoplasms; Calcitriol; Cell Division; Cell Line; Cholecalciferol; DNA-Binding Proteins; Dose-Response Relationship, Drug; Female; Gene Expression; Genes, Reporter; Humans; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Calcitriol; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad3 Protein; Thymidine; Trans-Activators; Transfection; Transforming Growth Factor beta

We investigated the effects of a nuclear receptor system constituted by retinoid X receptor (RXR) and its heterodimer partner on the aromatase activity in a cultured MCF-7 human breast cancer cell line and also in human ovarian granulosa cells, using each selective ligand for retinoic acid receptor, RAR (TTNPB), retinoid X receptor, RXR (LG100268), PPARgamma (troglitazone), and vitamin D3 receptor (cholecalciferol). In MCF-7 cells, the combined treatment with TTNPB and LG100268 caused a dramatic stimulation of the aromatase activity. The combined treatment with other ligand and LG100268 had little or no effect on the aromatase activity. The increase in the aromatase activity by TTNPB plus LG100268 was accompanied by an increase in the P450arom mRNA levels, which was also found to be related to the specific usage of promoter 1a of the CYP19 gene. These results suggest that a nuclear receptor system constituted by a RAR:RXR heterodimer is involved in the regulation of aromatase activity in MCF-7 breast cancer cells. In cultured human ovarian granulosa cells obtained from patients who underwent in vitro fertilization, troglitazone or LG100268 alone decreased the aromatase activity, while the combined treatment caused an even greater reduction in this activity. Little effect of other specific ligands for RXR heterodimer partners may support the notion that the effects of troglitazone and/or LG100268 in human granulosa cells may be mediated through the specific activation of PPARgamma:RXR heterodimer system. Since similar manners of effects of several PPARgamma ligands and/or LG100268 on the aromatase activity were observed in a newly established human ovarian granulosa cancer cell line, KGN, we performed the detailed analysis of the mechanisms of these effects using this cell line. As a result, the inhibitory effect of aromatase activity by troglitazone plus LG100268 was accompanied by the decrease of P450arom mRNA level. Furthermore, the loss of P450arom expression was considered to be due to both the decreased transcription and rapid degradation of its RNA based on the studies of nuclear run-on assay and RNA stability assay. In conclusion, RAR:RXR and PPARgamma:RXR heterodimer nuclear receptor systems may be other important modulators of estrogen production in human breast cancer cells and ovarian granulosa cells, respectively.

Topics: Aromatase; Benzoates; Breast Neoplasms; Cholecalciferol; Chromans; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Granulosa Cells; Humans; Ligands; Nicotinic Acids; Receptors, Calcitriol; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; RNA, Messenger; RNA, Neoplasm; Tetrahydronaphthalenes; Thiazoles; Thiazolidinediones; Transcription Factors; Troglitazone; Tumor Cells, Cultured

The biological activity of two novel 14-epi-analogues of 1,25(OH)2D3, 19-nor-14-epi-23-yne-1,25(OH)2D3 (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25(OH)2D3 (TX 527), is described. Both analogues were at least 10 times more potent than 1,25(OH)2D3 in inhibiting in vitro cell proliferation and had much lower in vivo calcemic effects than 1,25(OH)2D3. Treatment with 1,25(OH)2D3, TX 522, or TX 527 in vitro was accompanied by an accumulation of cells in the G1 phase of the cell cycle. Protein levels of cyclin C and cyclin D1 in in vitro cultures of MCF-7 cells were down-regulated to 50 and 30%, respectively, of control levels at 72 and 120 h after stimulation. Protein levels of p21 and p27 at 72 h were significantly enhanced by 1,25(OH)2D3 and TX 522 but surprisingly not by TX 527. The inability of TX 527 to up-regulate p21 seemed to be cell type specific because p21 was induced in other cell types. Diminished phosphorylation of the retinoblastoma protein after treatment with 1,25(OH)2D3, TX 522, or TX 527 may ultimately contribute to the growth inhibition caused by these compounds. According to the data presented, the induction of apoptosis seemed not to be a major mechanism responsible for the growth-inhibitory effect of 1,25(OH)2D3 and analogues. Both 14-epianalogues significantly retarded tumor progression (40% reduced compared with control mice) in an in vivo model of MCF-7 breast cancer cells established in nude mice. In conclusion, these novel analogues have the eligible profile to be tested as therapeutic agents for the treatment of hyperproliferative diseases such as breast cancer.

Topics: Alkynes; Animals; Apoptosis; Breast Neoplasms; Cell Division; Cholecalciferol; Cyclin C; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Cyclins; Female; G1 Phase; Humans; Mice; Mice, Nude; Neoplasm Proteins; Proto-Oncogene Proteins; Receptors, Calcitriol; Receptors, Estrogen; Retinoblastoma Protein

To gain insight into the molecular regulation of the human vitamin D3 receptor (hVDR), we have cloned and sequenced the 5' flanking region of exon 1c and examined promoter activity of this region in breast cancer cells. Sequence analysis of the first 1300 bp upstream of exon 1c reveals several characteristics of a class II promoter, including GC-rich regions and the presence of a TATA box at -29 bp. Putative transcription factor binding sites identified in this potential hVDR promoter include AP-2, Sp-1, and glucocorticoid response elements. No consensus vitamin D3 (VDRE) or estrogen (ERE) responsive elements were identified in the promoter sequence. Primer extension analysis performed with a primer specific for exon 1c confirms that transcription initiated in the 5' flanking region of exon 1c occurs in MCF-7 cells. Transient transfection of MCF-7 cells with this putative promoter region cloned into the pRLnull luciferase reporter vector generates significant reporter gene activity that is enhanced by treatment with forskolin, retinoic acid, and 17beta-estradiol. The enhancement of exon 1c promoter activity by 17beta-estradiol is blocked by the selective estrogen response modifier (SERM) tamoxifen and is not observed in estrogen receptor-negative breast cancer cells. In summary, we have cloned and characterized a TATA containing promoter upstream of exon 1c of the hVDR and provide evidence that this region represents a hormonally regulated hVDR promoter.

Topics: Base Sequence; Binding Sites; Breast Neoplasms; Cholecalciferol; Colforsin; Estradiol; Estrogen Antagonists; Estrogens; Exons; Gene Expression Regulation; Hormones; Humans; Molecular Sequence Data; Promoter Regions, Genetic; Receptors, Calcitriol; Response Elements; Tamoxifen; TATA Box; Transcription Factors; Transfection; Tretinoin; Tumor Cells, Cultured

To assess the modulating effects of vitamin D3, combined with or without tamoxifen, on cell proliferation and EGFR mRNA level of human breast cancer.. Two breast cancer cell lines (MCF-7 and ZR-75-1) were treated with various concentrations of vitamin D3, alone or in combination with tamoxifen, for 6 days. Cell proliferation was assessed by MIT uptake and EGFR mRNA level by Northern blot.. 10(-10)-10(-7) mol/L vitamin D3 strongly inhibited proliferation of the 2 breast cancer lines, while 10(-9)-10(-7) mol/L tamoxifen stimulated proliferation of MCF-7 cell. The growth inhibitory effect on the 2 cell lines could be augmented and accompanied by a decrease in EGFR mRNA level after combined treatment with IC50 dose of tamoxifen and 10(-10)-10(-9) mol/L vitamin D3.. Vitamin D3 can be considered as a useful anti-tumor drug in the treatment of breast cancer.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Division; Cholecalciferol; Drug Interactions; ErbB Receptors; Gene Expression; Humans; RNA, Messenger; Tamoxifen; Tumor Cells, Cultured

Nuclear steroid/retinoid and memgbrane c-erbB receptor tyrosine kinase signaling control proliferation and differentiation of mammary epithelial cells. Recently, we reported that retinoic acids are efficient repressors of c-erbB-2 and -3, but not of c-erbB-1 gene expresson. Here we demonstrate that retinoid acid- mediated growth inhibition is accompanied with reduced expression of c-erbB-4/HER4 in T47D breast cancer cells as determined by FACS, Western, and RT-PCR. All-trans and 9-cis retinoic acid reduce c-erbB-4 expression to 30%-60% of control, depending on the concentration. Dexamethasone (Dex) is inactive on D3 (D3), in contrast, acts as a strong inducer, elevation more that twofold at the mRNA, but does not significantly affect cell growth. We concolude that retinoic acids are efficient growth inhibitors and repressors of cell growth and c-erbB-4, whereas D3 represents a highly efficient inducer of c-erbB-4 expression with affecting cell proliferation.

Topics: Base Sequence; Blotting, Western; Breast Neoplasms; Cell Division; Cholecalciferol; Dexamethasone; DNA Primers; ErbB Receptors; Gene Expression Regulation, Neoplastic; Receptor, ErbB-4; Retinoids; RNA, Messenger; Tumor Cells, Cultured

The 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is the physiologically active form of vitamin D3 that inhibits proliferation and induces differentiation of a variety of malignant cells. We evaluated a newly synthesized vitamin D3 analogue [1,25(OH)2-16-ene-5,6-trans-D3 (Ro 25-4020)] that has a novel 5,6-trans motif. Dose-response studies showed that 1,25(OH)2-16-ene-5,6-trans-D3 had 10-100-fold greater antiproliferative activities than 1,25(OH)2D3 when measuring clonal growth of breast (MCF-7) and prostate (LNCaP) cancer cell lines as well as a myeloid leukemia cell line (HL-60). Because the chief toxicity of vitamin D3 is hypercalcemia, we examined the calcemic activity of 1,25(OH)2-16-ene-5,6-trans-D3 in mice. Remarkably, 1,25(OH)2-16-ene-5,6-trans-D3 was at least 40-fold less calcemic as compared with 1,25(OH)2D3 and 1,25(OH)2-16-ene-D3 (Ro 24-2637). To explore the mechanism by which the 1,25(OH)2-16-ene-5,6-trans-D3 analogue mediated its antiproliferative activity, several studies were performed. Pulse-exposure studies showed that a 4-day pulse exposure to 1,25(OH)2-16-ene-5,6-trans-D3 (10(-7) M) in liquid culture was adequate to achieve a 40% inhibition of MCF-7 clonal growth in the absence of the analogue, suggesting that the growth inhibition mediated by 1,25(OH)2-16-ene-5,6-trans-D3 was at least in part irreversible. Cell cycle studies showed that 1,25(OH)2-16-ene-5,6-trans-D3 increased the proportion of MCF-7 cells in the G0-G1 phase and decreased those in the S phase. Furthermore, 1,25(OH)2-16-ene-5,6-trans-D3 induced an elevated expression of the cyclin-dependent kinase inhibitors, p21waf1 and p27kip1. In addition, 1,25(OH)2-16-ene-5,6-trans-D3 almost completely inhibited telomerase activity, as measured by telomeric repeat amplification protocol assay and human telomerase reverse transcriptase mRNA. For each of the growth-related parameters that were examined, the vitamin D3 analogue was more active than 1,25(OH)2D3. In contrast, 1,25(OH)2D3 was more calcemic than 1,25(OH)2-16-ene-5,6-trans-D3. In summary, 1,25(OH)2-16-ene-5,6-trans-D3, having a novel 5,6-trans motif, strongly inhibited clonal proliferation and reduced telomerase activity with low calcemic activity, suggesting further testing in in vivo cancer models. This analogue may gain a therapeutic niche for selected malignancies.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Division; Cholecalciferol; Female; Humans; Leukemia, Myeloid; Male; Mice; Prostatic Neoplasms; Tumor Cells, Cultured

In view of the tumor suppressor role of the transforming growth factor-beta (TGFbeta) type II receptor (RII), the identification and characterization of agents that can induce the expression of this receptor are of potential importance to the development of chemoprevention approaches as well as treatment of cancer. To date, the identification of exogenous agents that control RII expression has been rare. We demonstrated that proliferation of MCF-7 early passage cells (MCF-7 E), which express RII and are sensitive to TGFbeta growth inhibition activity, was significantly inhibited by vitamin D3 and its analogue EB1089. In contrast, proliferation of MCF-7 late passage cells (MCF-7 L), which have lost cell surface RII and are resistant to TGFbeta, was not affected by these two compounds. TGFbeta-neutralizing antibody was able to block the inhibitory effect on MCF-7 E cells by these compounds, indicating that treatment induced autocrine-negative TGFbeta activity. An RNase protection assay showed approximately a 3-fold induction of the RII mRNA, while a receptor cross-linking assay revealed a 3-4-fold induction of the RII protein. In contrast, there was no change in either RII mRNA or protein in the MCF-7 L cells.

Topics: Antineoplastic Agents; Breast Neoplasms; Calcitriol; Cholecalciferol; DNA Replication; Female; Gene Expression Regulation, Neoplastic; Humans; Kinetics; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Tumor Cells, Cultured

Our studies have identified 1,25(OH)2D3 as a coordinate regulator of proliferation and apoptosis in breast cancer cells. In MCF-7 cells, 1,25(OH)2D3 down regulates the estrogen receptor (ER), suggesting that the effects of 1,25(OH)2D3 may be linked to disruption of estrogen regulated survival signals. Although studies have demonstrated that 1,25(OH)2D3 inhibits growth of ER negative breast cancer cells, previous data were generated by comparison of cell lines derived from heterogeneous human tumors and harboring diverse genetic alterations. To provide more conclusive evidence for independent growth regulatory pathways mediated by antiestrogens and 1,25(OH)2D3, we examined vitamin D3 sensitivity in MCf-7 cells selected for resistance to ICI 182, 780 (Zeneca, Macclesfield, UK). The clones we selected for resistance to ICI 182,780 retain functional VDR and undergo 1,25(OH)2D3 mediated growth arrest and apoptosis, in vitro and in vivo, despite loss of estrogen dependence. Cell cycle data indicate that treatment of parental or anti-estrogen resistant MCF-7 clones with 1,25(OH)2D3, in the presence or absence of ICI 182,780, increases the percentage of cells in G0/G1 while reducing the number of cells in S phase. In addition, 1,25(OH)2D3 induces characteristic features of apoptosis, including DNA fragmentation, in both parental and anti-estrogen resistant MCF-7 cells. Furthermore, we report that cells selected for vitamin D3 resistance retain sensitivity to ICI 182,780 mediated growth arrest and apoptosis. This work emphasizes that vitamin D3 compounds and anti-estrogens trigger growth arrest and apoptosis in breast cancer cells by distinct mechanisms, and that breast cancer cell sensitivity to 1,25(OH)2D3 is not diminished during the progression to estrogen independence.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle; Cholecalciferol; DNA Fragmentation; Estradiol; Estrogen Antagonists; Fulvestrant; Growth Substances; Humans; Receptors, Calcitriol; Receptors, Estrogen; Tumor Cells, Cultured

1. 1alpha,25-dihydroxyvitamin3 (VD) is a nuclear hormone that has important cell regulatory functions but also a strong calcemic effect. EB1089 is a potent antiproliferative VD analogue, which has a modified side chain resulting in increased metabolic stability and a selective functional profile. Since EB1089 is considered for potential systemic application, it will be investigated to what extent its recently identified metabolites (hydroxylated at positions C26 and C26a) contribute to biological profile of the VD analogue. 2. Limited protease digestion analysis demonstrated that EB1089 is able to stabilize the high affinity ligand binding conformation of the VDR, starting at concentrations of 0.1 nM and affecting up to 80% of all receptor molecules. The metabolites EB1445 and EB1470 showed to be 100 fold less potent than EB1089, whereas the remaining three metabolites (EB1435, EB1436 and EB1446) showed a clearly reduced ability to stabilize the high affinity ligand binding conformation. Interestingly, at pharmacological concentrations all EB1089 metabolites stabilized a second, apparently lower affinity conformation to a much higher extent than EB1089. 3. In reporter gene assays all metabolites showed lower potency than EB1089. Moreover, the preference of EB1089 for activation of VDR binding to sites formed by inverted palindromic arrangements spaced by nine nucleotide (IP9-type VD response elements) appeared to be reduced (with EB1445 and EB1470) or completely lost (with EB1435, EB1436 and EB1446). The ranking of EB1089 and its metabolites that was obtained by limited protease digestion and reporter gene assays was confirmed by an analysis of their antiproliferative effect in breast cancer cells. . The potency and selectivity of the EB1089 metabolites in mediating gene regulatory effects was found to be drastically reduced in comparison to the parent compound suggesting that the contribution of the metabolites to the biological effect of EB1089 is minor. However, the compounds showed to be interesting tools for understanding the selective biological profile of EB1089.

Topics: Antineoplastic Agents; Breast Neoplasms; Calcitriol; Carcinogens; Cholecalciferol; Female; Humans; Ligands; Protein Conformation; Receptors, Calcitriol; Transfection; Tumor Cells, Cultured

The seco-steroid hormone, 1 alpha, 25 dihydroxyvitamin D3 (1 alpha,25(OH)2D3) binds to a specific nuclear receptor that acts as a ligand-inducible transcription factor. The resulting genomic effects include partial arrest in G0/G1 of the cell cycle and induction of differentiation; these effects have been observed in various types of cancer. Recently, we produced enzymatically the natural 24-oxo metabolites of 1 alpha,25(OH)2D3 and two of its potent synthetic analogs (1 alpha,25-(OH)2-16-ene-D3 and 1 alpha,25-(OH)2-20-epi-D3) using a rat kidney perfusion system. We have found that the 24-oxo metabolites of both 1 alpha,25(OH)2D3 and its analogs have either the same or greater antiproliferative activity against various cancer cells as their parental compounds. Notably, two cell lines (DU-145 (prostate cancer) and MDA-MB-436 [breast cancer]) that were extremely resistant to the antiproliferative effects of vitamin D3 analogs displayed greater sensitivity towards the 24-oxo metabolite of the vitamin D3 analog. Similarly, the 24-oxo metabolites had the capacity to induce differentiation and apoptosis and to diminish the proportion of cells in S phase. Most interestingly, while the analog 1 alpha,25(OH)2-20-epi-D3 induced expression of BRCA1 in MCF-7 breast cancer cells; its 24-oxo metabolite dramatically suppressed BRAC1 expression. Thus, we have shown for the first time that the various biological activities produced by the hormone 1 alpha,25(OH)2D3 and some of its analogs may represent a combination of actions by the hormone 1 alpha,25(OH)2D3 and its natural 24-oxo metabolites.

Topics: Apoptosis; bcl-2-Associated X Protein; BRCA1 Protein; Breast Neoplasms; Cadherins; Calcitriol; Cell Cycle; Cell Cycle Proteins; Cell Division; Cholecalciferol; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; HL-60 Cells; Humans; Male; Microtubule-Associated Proteins; Neoplasms; Prostatic Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured; Tumor Suppressor Proteins

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3), the active form of vitamin D3, and tetradecanoylphorbol acetate (TPA) are potent negative growth regulators of breast cancer cells. In this study, we compared the mechanism of action of these two compounds in MCF-7 cells and a vitamin D3-resistant variant (MCF-7D3Res). In parental MCF-7 cells, 1,25-(OH)2D3 induced morphological and biochemical markers of apoptosis (chromatin and nuclear matrix condensation and DNA fragmentation), whereas TPA induced growth arrest without apoptosis. Both 1,25-(OH)2D3 and TPA independently up-regulated the vitamin D receptor, p21, and the hypophosphorylated form of retinoblastoma (Rb) protein. The growth regulatory effects of 1,25-(OH)2D3 and TPA did not correlate with induction of p53 protein expression. When both compounds were added simultaneously, synergistic effects on MCF-7 cell number were observed, and cell cycle regulatory proteins were down-regulated. The MCF-7D3Res cells, which are not sensitive to 1,25-(OH)2D3, were growth inhibited by TPA, and TPA partially sensitized MCF-7D3Res cells to the growth inhibitory effects of 1,25-(OH)2D3. In MCF-7D3Res cells, 1,25-(OH)2D3 treatment had minimal effects on p21 or Rb protein expression, whereas TPA down-regulated Rb protein and transiently up-regulated p21. These studies indicate dissociation between the pathways triggered by 1,25-(OH)2D3 and TPA, which mediate growth regulation in MCF-7 cells. Because both compounds induce growth arrest, but only 1,25-(OH)2D3 mediates apoptosis, we conclude that cell cycle arrest is not sufficient to trigger cell death of MCF-7 cells, and that 1,25-(OH)2D3 generates distinct signals which lead to induction of apoptosis in breast cancer cells.

Topics: Apoptosis; Breast Neoplasms; Calcitriol; Cell Count; Cell Cycle; Cell Cycle Proteins; Cholecalciferol; Drug Resistance; Female; Genetic Variation; Humans; Receptors, Calcitriol; Receptors, Estrogen; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Breast cancer cells express vitamin D3 receptors and 1,25-dihydroxyvitamin D3 suppressed growth of these cells. We have synthesized six novel vitamin D3 analogues to identify those with expanded capacity to inhibit the proliferative ability of breast cancer cells. These analogues incorporated many of the structural motifs shown previously to have antiproliferative activity in several cell types. Six breast cancer cell lines were used as targets. Dose-response studies showed that each of the analogues had antiproliferative activities, and LH [1,25-(OH)2-16-ene-23-yne-26,27-F6-19-nor D3] was the most potent analogue, suppressing at 10(-11) M greater than 50% clonal proliferation (ED50) of the MCF-7 and SK-BR-3 breast cancer cells, increasing the proportion of MCF-7 cells in the G0-G1 phase, and decreasing those in the S phase of the cell cycle. Pulse-exposure studies showed that a 3-day exposure to LH (10(-7) M) in liquid culture was adequate to achieve a 50% inhibition of MCF-7 clonal growth in soft agar in the absence of the analogue, suggesting that the growth inhibition mediated by LH is irreversible. The cyclin-dependent kinase inhibitor known as p27Kip1 helps regulate the cell cycle and can mediate growth arrest in response to extracellular growth inhibitors. The analogue LH (10(-7) M) induced elevated expression of p27Kip1 in MCF-7 and SK-BR-3 cells. Taken together, these results indicate that LH is an extremely potent vitamin D3 analogue markedly inhibiting clonal growth of MCF-7 and SK-BR-3 cells with concomitant cell cycle arrest at G0-G1 and increased expression of p27Kip1. Compound LH is worthy of in vivo analysis for possible future clinical trials.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Cycle; Cell Division; Cholecalciferol; Dose-Response Relationship, Drug; Female; Humans; Structure-Activity Relationship; Tumor Cells, Cultured

Examination of a panel of ER positive breast cancer cell lines showed that they were differentially growth inhibited by vitamin D3 and its analogue EB1089. EB1089 treatment of the breast cancer cell lines MCF-7 E, BT20, T47D, and ZR75 demonstrated a correlation between a reduction in Cdk2 kinase activity towards phosphorylation of histone H1 and a decrease in DNA synthesis, while no modulation of Cdk2 activity was observed in the vitamin D3 and EB1089 resistant cell line MCF-7 L. This was accompanied by a time dependent decrease in the percentage of S phase cells in the responsive lines. Characterization of the expression levels of Cdk2 and its related cell cycle proteins in MCF-7 E cells showed that after EB1089 treatment, there was a concentration and time dependent up-regulation of p21 as well as a decrease in cyclin A proteins. Paradoxically, cyclin E levels were increased as a function of treatment. Analysis of cyclin-Cdk2-Cdki complex formation showed that in EB1089 treated MCF-7 E cells, Cdk2, cyclin A and cyclin E immunoprecipitates contained an increased abundance of p21. In contrast to MCF-7 E cells, increases in both p21 and p27 as well as their complex formation with Cdk2 were observed in BT20 and ZR75 cells. These findings indicate that up-regulation of p21 as well as p27 in some cell types may account for the inactivation of Cdk2 activity and a G1 block of the cell cycle following EB1089 treatment.

Topics: Antineoplastic Agents; Breast Neoplasms; Calcitriol; CDC2-CDC28 Kinases; Cell Cycle; Cell Cycle Proteins; Cholecalciferol; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; Cyclins; DNA, Neoplasm; Humans; Microtubule-Associated Proteins; Protein Serine-Threonine Kinases; Tumor Cells, Cultured; Tumor Suppressor Proteins; Up-Regulation

The principal cause of death from most forms of cancer is metastatic disease. Cancer cells appear to grow quickly out of the control of the normal host regulatory mechanisms. Many factors contribute to this unrestrained proliferation, including increased metalloproteinase activity causing degradation of the extracellular matrix surrounding cancer cells, angiogenesis permitting easy access of the cells to the bloodstream and decrease or loss of programmed cell death, or apoptosis, an important mechanism for removal of abnormal or senescent cells. Treatment modalities targeted towards arresting cancer cell proliferation and spread are needed to improve the survival of patients with cancer. Vitamin D3, 1,25-dihydroxychole-calciferol D3, has been shown to induce apoptosis in the human breast cancer cell line, MCF-7. We have studied the effects of three concentrations of vitamin D3 on the human breast cancer cell line, MDA-MB-435, the human prostate cancer cell line, LNCaP, and a human osteosarcoma cell line, U20S. We report here that vitamin D3 strikingly inhibits cell proliferation and induces apoptosis in all three cell lines.

Topics: Adenocarcinoma; Apoptosis; Breast Neoplasms; Cell Division; Cholecalciferol; Dose-Response Relationship, Drug; Female; Humans; Male; Neoplasm Proteins; Osteosarcoma; Prostatic Neoplasms; Tumor Cells, Cultured

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3], the active metabolite of vitamin D3, is a potent inhibitor of breast cancer cell growth both in vivo and in vitro. We have previously demonstrated that 1,25-(OH)2D3 induces morphology (pyknotic nuclei, chromatin and cytoplasmic condensation, and nuclear matrix protein reorganization) consistent with the activation of apoptosis in MCF-7 cells. These morphological changes in 1,25-(OH)2D3-treated cells are associated with up-regulation of TRPM-2/clusterin and cathepsin B (genes associated with mammary gland apoptosis) and down-regulation of bcl-2, an antiapoptotic gene. Thus, the inhibitory effects of 1,25-(OH)2D3 on MCF-7 cell growth involve activation of apoptosis. To investigate the mechanisms by which vitamin D3 activates apoptosis, we have selected a vitamin D3-resistant variant (MCF-7D3Res cells) by continuous culture of MCF-7 cells in 100 nM 1,25-(OH)2D3. The MCF-7D3Res cells represent a stably selected phenotype that grows equally well with or without 100 nM 1,25-(OH)2D3. In contrast to the MCF-7 cells from which they were derived (MCF-7WT cells), MCF-7D3Res cells do not exhibit apoptotic morphology, DNA fragmentation, or up-regulation of apoptosis-related proteins after treatment with 1,25-(OH)2D3. MCF-7D3Res cells exhibit cross-resistance to several vitamin D3 analogs that are potent growth regulators of MCF-7WT cells. MCF-7WT and MCF-7D3Res cells exhibit comparable sensitivity to induction of apoptosis and up-regulation of clusterin in response to the antiestrogen 4-hydroxytamoxifen. MCF-7D3Res cells express comparable levels of the vitamin D receptor (VDR), as assessed by Western blotting or ligand binding, as MCF-7WT cells. In both sensitive and resistant cell lines, 1,25-(OH)2D3 up-regulates whereas 4-hydroxytamoxifen down-regulates VDR protein expression, indicating appropriate homologous and heterologous VDR regulation in MCF-7D3Ras cells. Gel shift analyses indicate that nuclear extracts from MCF-7WT and MCF-7D3Res cells bind equally well to the DR3 consensus vitamin D3 response element. These data suggest that MCF-7D3Res cells have a functional VDR that is uncoupled from a functional apoptotic pathway. MCF-7D3Res cells offer a unique model system for identification of the mechanisms by which vitamin D3 regulates the cell death pathway in breast cancer cells.

Topics: Apoptosis; Breast Neoplasms; Calcitriol; Cathepsin B; Cell Death; Cell Division; Cholecalciferol; Clusterin; Complement Inactivator Proteins; Drug Resistance, Neoplasm; Estrogen Antagonists; Glycoproteins; Humans; Molecular Chaperones; Neoplasm Proteins; Receptors, Calcitriol; Signal Transduction; Tumor Cells, Cultured; Vitamin D

Vitamin-D3 derivatives are now well-recognized growth inhibitors of numerous tumoral cells and in particular breast-cancer cells. However, the mechanisms by which they operate are not well established. Among the wide range of physiological and biological functions of vitamin-D3 derivatives, the best described include their action on calcium homeostasis. In this study, we sought to establish whether the effects of vitamin-D3 derivatives on breast-cancer cell growth may be in part related to intracellular calcium modulation and induction of apoptosis. To address these questions, we used, in addition to 1,25(OH)2D3, the active metabolite of vitamin D3, a non-calcemic 1,25(OH)2D3 derivative: Ro 23-7553 [16-ene-23-yne-1,25(OH)2D3], which in our hands was more potent than the parent compound in inhibiting breast-cancer cell growth. We showed that the efficiency of both compounds in growth inhibition was higher in the estradiol-receptor-positive-breast-tumor MCF-7 cells than in the estradiol-receptor-negative MDA-MB 231 cells. In MCF-7 cells in particular, important modifications of intracellular calcium related to the emptying of intracellular pools were observed. The depletion of Ca++ from intracellular stores was followed by the induction of apoptosis. Such a phenomenon was never observed in MDA-MB 231 cells. Our results suggest that the action of vitamin-D3 derivatives on the depletion of calcium stores, which was more significant in MCF-7 than in MDA-MB 231 cells, may induce apoptosis in the former cells and account for the high efficiency of vitamin-D3 derivatives on growth inhibition of MCF-7 breast-tumor cells.

Topics: Apoptosis; Breast Neoplasms; Calcitriol; Calcium; Calcium Channels; Cell Division; Cholecalciferol; Humans; Tumor Cells, Cultured

The aromatase and estrone sulfatase enzymes are important sources of biologically active estrogens in postmenopausal women with breast cancer. Promising initial results in the treatment of endocrine-responsive breast cancer have been exhibited by 1 alpha 25-dihydroxyvitamin D3 and the synthetic vitamin D analogues MC903 and EB1089. However, these compounds together with vitamin D3 and vitamin D3 sulfate did not inhibit the human placental aromatase enzyme when assayed up to 20 microns. Only vitamin D3 sulfate and 1 alpha 25-dihydroxyvitamin D inhibited the estrone sulfatase activity in human placental microsomes, albeit at high concentration (32 and 37% inhibition, respectively with 50 microns each inhibitor). It is unlikely that inhibition of aromatase or estrone sulfatase enzymes contribute to the inhibitory effect of this group of compounds on breast cancer cells in vivo.

Topics: Aromatase Inhibitors; Breast Neoplasms; Cholecalciferol; Female; Humans; Placenta; Pregnancy; Sulfatases

Topics: Ascorbic Acid; Breast Neoplasms; Cholecalciferol; Fatty Acids; Feeding Behavior; Female; Humans; Neoplasms; Nutritional Requirements; Risk Factors; Vitamin A

Topics: Adult; Aged; Breast Neoplasms; Calcium; Cholecalciferol; Female; Humans; Middle Aged; Receptors, Steroid

Eleven of twelve human breast cancers contained a lipid which increased urinary (45)Ca and (40)Ca excretion of (45)Ca-labeled, parathyroidectomized rats receiving a low Ca diet. The lipid has mobility on thin-layer chromatography and gas-liquid chromatography close to, but not identical with, that of 7-dehydrocholesterol. Authentic 7-dehydrocholesterol has osteolytic activity similar to that of the extracted sterol. Fluorescence and Lieberman-Burchard reactions of the extracted sterol are similar to those of 7-dehydrocholesterol. The lipid was found by thin-layer chromatography in the extracts which had osteolytic activity. Neither the lipid nor osteolytic activity was found in extracts of tissue from two normal human breasts.

Topics: Animals; Breast Neoplasms; Calcium; Calcium Isotopes; Cholecalciferol; Chromatography, Gas; Chromatography, Thin Layer; Decalcification, Pathologic; Female; Fluorescence; Humans; In Vitro Techniques; Radiometry; Rats; Sterols; Urine; Vitamin D