oxytocin and Breast-Neoplasms

Recent data demonstrate the anabolic effect of oxytocin on bone. Bone cells express oxytocin receptors. Oxytocin promotes osteoblasts differentiation and function, leading to an increased bone formation with no effect on bone resorption and an improvement of bone microarchitecture. Oxytocin is synthetized by osteoblasts, and this synthesis is stimulated by estrogen. Animal studies demonstrate a direct action of oxytocin on bone, as the systemic administration of oxytocin prevents and reverses the bone loss induced by estrogen deficiency. Although oxytocin is involved in bone formation in both sexes during development, oxytocin treatment has no effect on male osteoporosis, underlining the importance of estrogen that amplifies its local autocrine and paracrine secretion. There are few human data showing a decrease in the oxytocin serum level in anorexia nervosa independently of estrogen and in amenorrheic women associated with impaired bone microarchitecture; in post-menopausal women a higher oxytocin serum level is associated with higher bone density, but not in osteoporotic men. Oxytocin displays many effects that may be beneficial in the management of osteoporosis, cardiovascular diseases, cognitive disorders, breast cancer, diabetes and body fat gain, all age-related diseases affecting elderly women, opening exciting therapeutic perspectives, although the issue is to find a single route, dosage and schedule able to reach all these targets.

Topics: Amenorrhea; Animals; Anorexia Nervosa; Autocrine Communication; Bone and Bones; Bone Density; Breast Neoplasms; Cardiovascular Diseases; Cognitive Dysfunction; Diabetes Mellitus; Estrogens; Female; Humans; Male; Osteoporosis, Postmenopausal; Oxytocin; Paracrine Communication; Sex Characteristics

Breast cancer is making up one-quarter of all new female cancer cases diagnosed worldwide. Breast cancer surgeries, radiation therapies, cytotoxic chemotherapies and targeted therapies have made significant progress and play a dominant role in breast cancer patient management. However, many challenges remain, including resistance to systemic therapies, tumour recurrence and metastasis. The cyclic neuropeptide oxytocin (OT) elicits a plethora of biological responses via the oxytocin receptor (OTR) in both the central and peripheral nervous system, including social bonding, stress, maternal behaviour, sexual activity, uterus contraction, milk ejection and cancer. As a typical member of the G protein-coupled receptor family, OTR represents also an intriguing target for cancer therapy. There is emerging evidence that OTR plays a role in breast cancer development and progression, and several breast cancer cell lines express OTR. However, despite supporting evidence that OT lowers breast cancer risks, its mechanistic role in breast cancer development and the related signalling pathways are not fully understood. Here, we review the current knowledge of the OT/OTR signalling system in healthy breast tissue as well as in breast cancer, and discuss OTR as a potential therapeutic target for breast cancer management.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Transformation, Neoplastic; Chemoprevention; Disease Management; Disease Models, Animal; Disease Susceptibility; Drug Evaluation, Preclinical; Female; Gene Expression Regulation, Neoplastic; Humans; Ligands; Molecular Targeted Therapy; Oxytocin; Receptors, Estrogen; Receptors, Oxytocin; Signal Transduction

Social environment is a well-recognized determinant in health and wellbeing. Among breast cancer patients, inadequate social support is associated with a substantial increase in cancer-related mortality. A common explanation is that socially isolated individuals fare worse due to reduced instrumental support (i.e., assistance meeting the demands of treatment). However, the ability to replicate the detrimental effects of social isolation on mammary tumor growth in rodents strongly suggests an alternative explanation; i.e., socially isolated individuals have a physiological milieu that promotes tumor growth. This review summarizes the clinical and basic science literature supporting social influences on breast cancer, and provides a conceptual physiological framework for these effects. We propose that social environment contributes to the vast individual differences in prognosis among breast cancer survivors because social environment is capable of altering basic physiological processes, which in turn can modulate tumor growth. Appreciation of the role of social environment in breast cancer progression could promote the identification of patients at increased risk for poor outcomes. In addition, characterization of the underlying physiological mechanisms could lead to targeted disruption of detrimental pathways that promote tumor progression in socially isolated individuals, or exploitation of protective pathways activated through social engagement as novel therapeutic complements to contemporary treatments.

Topics: Breast Neoplasms; Disease Progression; Disease Susceptibility; Female; Health Impact Assessment; Humans; Mammary Neoplasms, Experimental; Oxytocin; Signal Transduction; Social Change; Social Environment; Social Isolation; Stress, Physiological; Stress, Psychological

Lack of sensitivity and specificity of image-based breast cancer screening has urged the exploration of alternate screening modalities. Nipple fluid, which contains breast epithelial cells, is produced in small amounts in the breast ducts of nonlactating women and can be collected by noninvasive vacuum aspiration. After administration of nasal oxytocin, nipple aspiration yields sufficient material for molecular analysis in the large majority of women. Whereas nipple fluid cytology appears to have only a moderate correlation with breast cancer development, methylation holds promise as a more appropriate biomarker, since methylation aberrations occur as an early and frequent event during carcinogenesis. Using quantitative multiplex methylation-specific PCR, methylation can be detected in minute amounts of DNA extracted from nipple aspirates, precluding the need for more invasive intraductal approaches such as ductal lavage and random periareolar fine needle aspiration. The application of genomic and proteomic diagnostics to nipple aspirates therefore provides unprecedented opportunities for early breast cancer diagnosis amendable to population-based screening.

Topics: Biopsy, Needle; Body Fluids; Breast Neoplasms; DNA; Epithelial Cells; Female; Humans; Mass Screening; Nipples; Oxytocin; Sensitivity and Specificity

Oxytocin (OT) plays a crucial role as a mediator of breast myoepithelial cell contraction, the process responsible for the ejection of milk during lactation, and is also involved in myoepithelial cell proliferation and postpartum mammary gland proliferation. Furthermore, although a number of breast cancer cells have oxytocin receptors (OTRs), it has been reported that OT stimulates, inhibits, or has no effect on cell proliferation. As these different effects seem to be mediated by different signaling pathways elicited by OTR stimulation, we here review the regulation of OTR signaling in different cell systems and discuss how understanding the molecular basis of receptor coupling specificity has become extremely important for understanding the role played by OTRs in regulating cell growth.

Topics: Animals; Breast; Breast Neoplasms; Epithelial Cells; Epithelium; Female; Gene Expression Regulation; Humans; Lactation; Mammary Glands, Animal; Mammary Neoplasms, Animal; Membrane Microdomains; Muscle Cells; Oxytocin; Receptors, Oxytocin; Signal Transduction; Tumor Cells, Cultured; Vasotocin

Damage to the breast epithelium by chemical carcinogens as products of oxygen free radical release can lead to fibroblast proliferation, hyperplasia of epithelium, cellular atypia and breast cancer. Chemical carcinogens may accumulate in breast fluid in the non-lactating breast consequent to superoxide free radical production which occurs via the adenosine triphosphate (ATP) hypoxanthine pathway. This pathway is initiated by hypoxia of local tissue. Under hypoxic conditions ATP is broken down to form hypoxanthine. Hypoxanthine itself is broken down to produce xanthine and then uric acid. This results in the production of superoxide free radicals, the products of which are carcinogenic. The development of localized hypoxia, which is central to this hypothesis, is caused by acinal gland distention from fluid secreted by raised prolactin levels in the absence of oxytocin. Stimulation of the nipple in a non-lactating breast may raise plasma oxytocin and lower plasma prolactin levels. Contraction of the myoepithelial cells of the breast under the influence of oxytocin would relieve distention of the acinal glands and thus reduce hypoxia and the generation of lipid peroxidoses as products of free radical damage. The epidemiology of breast fibrosis and cancer support the notion that lack of nipple stimulation over time may be a significant variable. A review of this literature linked with current biochemical work on fibrosis and carcinogenesis suggest that draining the breasts of the products of superoxide free-radical release by the encouragement of regular nipple erections may prevent such breast disease.

Topics: Breast; Breast Neoplasms; Female; Free Radicals; Humans; Lactation; Models, Biological; Oxytocin; Prolactin; Reproduction

The purpose of this study was to examine the effect of repeated effleurage massage treatments compared with a visit control group on circulating lymphocytes by studying the number and activity of peripheral blood NK cells, CD4+ and CD8+ T cells in women with breast cancer. Furthermore, the effect of repeated effleurage massage treatments on the levels of cortisol in saliva and oxytocin in plasma as well as degree anxiety, depression and quality of life was studied.. A single centre, prospective, randomized, controlled trial.. The study was conducted in a radiation department, in a hospital in south-western Sweden.. Twenty-two women (mean age=62) with breast cancer undergoing radiation were included in this study.. The patients were randomly assigned to effleurage massage therapy (20 min of effleurage on ten occasions) or to control visits (ten 20-minute visits).. Blood samples were collected before the first and last massage/control visit for analysis of peripheral blood NK, T cells and oxytocin. Saliva was analysed for cortisol. In addition, the patients completed the Hospital Anxiety and Depression Scale, Life Satisfaction Questionnaire and Spielbergers State Trait Anxiety Inventory prior to the first and last massage/control visit.. Effleurage massage treatment had no significant effect on the number, frequencies or activation state of NK cells or CD4+ or CD8+ T cells. Furthermore, no significant changes between groups were detected on cortisol and oxytocin concentrations, anxiety, depression or quality of life.. Significant effect of effleurage massage on cellular immunity, cortisol, oxytocin, anxiety, depression or quality of life could not be demonstrated in this study. Several possible explanations to the results of this study are discussed.

Topics: Aged; Aged, 80 and over; Anxiety Disorders; Breast Neoplasms; Carcinoma; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Depressive Disorder; Endocrine System; Female; Humans; Hydrocortisone; Immunity, Cellular; Killer Cells, Natural; Massage; Middle Aged; Mood Disorders; Oxytocin; Patient Satisfaction; Prospective Studies; Psychological Tests; Quality of Health Care; Quality of Life; Stress, Psychological; Treatment Outcome

Reduced emotional expression has been consistently related to susceptibility or fast progression of breast cancer. Breast cancer development and reduced emotional expression have both been related to rejection- and separation-related conditions. The neuropeptide oxytocin is low in response to rejection or separation. Recent results suggest that oxytocin may protect against the development of breast cancer and slow its progression. In the present study, we investigated if individual differences in emotional expressivity relate to basal or cortisol-stimulated plasma oxytocin. Healthy female subjects were treated with placebo or 35mg of cortisol orally in a double-blind within-subject study. Seventy minutes later, blood was sampled for determination of oxytocin and cortisol levels. We found an interaction between treatment condition and Emotional Expression-out scores: after cortisol treatment, oxytocin levels increased proportional to Emotion Expression-out score. These preliminary findings provide a potential mechanism for associations in the literature between emotional expressive behavior and breast cancer.

Topics: Adult; Affective Symptoms; Arousal; Breast Neoplasms; Communication; Double-Blind Method; Emotions; Fear; Female; Humans; Hydrocortisone; Individuality; Internal-External Control; Middle Aged; Oxytocin; Rejection, Psychology; Surveys and Questionnaires

Oxytocin is a neuropeptide released by the central nervous system. A number of studies have demonstrated the role of this neuropeptide in the pathogenesis of breast cancer. In the present project, we have identified mRNA coding genes and long non-coding RNAs (lncRNAs) that are associated with this pathway through an in-silico strategy, and measured their expression in a cohort of Iranian females affected with this type of malignancy. Expression levels of OXTR, FOS, ITPR1, RCAN1, CAMK2D, CACNA2D and lnc_ZFP161 were significantly down-regulated in breast cancer tissues compared with nearby non-cancerous tissues. On the other hand, expression of lnc_MTX2 was higher in breast cancer tissues compared with controls. Expression of lnc_TNS1 and lnc_FOXF1 were not different between these two kinds of samples. Expression of CACNA2D was associated with mitotic rate and PR status (P values = 3.02E-02 and 2.53E-02, respectively). Expression of other oxytocin-related genes was not associated with clinicopathological parameters. FOS and ITPR1 had the highest AUC value among the oxytocin-related genes. Combination of expression profiles of all oxytocin-related genes increased the AUC value to 0.75. However, the combinatorial sensitivity and specificity values were lower than some individual genes. In the breast cancer tissues, the most robust correlations have been detected between lnc_ZFP161/ lnc_FOXF1, CAMK2D/ lnc_ZFP161 and CAMK2D / lnc_FOXF1 (r = 0.86, 0.71 and 0.64 respectively). In the non-cancerous tissues, the strongest correlation was detected between lnc_FOXF1/lnc_MTX2 and lnc_ZFP161/CAMK2D respectively (r = 0.78 and 0.65). Taken together, oxytocin-associated genes have been dysregulated in breast cancer tissues. Moreover, the correlation ratio between these genes is connected with the existence of cancer.

Topics: Adult; Aged; Breast Neoplasms; Female; Gene Regulatory Networks; Humans; Inositol 1,4,5-Trisphosphate Receptors; Middle Aged; Oxytocin; Proto-Oncogene Proteins c-fos; RNA, Long Noncoding

The oxytocin receptor (OXTR) plays an important role in childbirth, breastfeeding, and social interactions. There is emerging evidence that OXTR is associated with the breast cancer (BC) initiation and progression. However, the mechanisms leading to a change in its expression, the diagnostic or prognostic value of the receptor in BC are currently poorly understood. Here, we have evaluated the relative level of OXTR expression in BC samples (n=107), and also investigated the effect of estradiol on its expression in MCF-7 and MDA-MB-231 cells. The level of OXTR expression was significantly lower in breast tumor tissue than in normal tissue obtained from the same patient. The expression of OXTR was dependent on the status and expression of the estrogen receptor (ER): the level of OXTR mRNA was significantly lower in ER-negative BC samples compared to ER-positive BC samples. Moreover, OXTR expression was also lower in samples from patients with luminal subtype with a low value of ER expression (0-5 score according to the IHC assay, Allred scoring) compared with samples with high ER expression (6-8 score). In luminal BC, OXTR expression was associated with the HER2 expression level: the OXTR mRNA level was higher in tumors with a HER2 IHC score of 1+ as compared to cases with the HER2 expression score of 2+, 3+. We also showed that estradiol increased the level of OXTR mRNA in MCF-7 cells, but not in ER-negative MDA-MB-231 cells. These data indicate that changes in OXTR expression in BC tissues can be caused by increased ER expression. We found no association between OXTR and T or N stages and progesterone receptor expression.. Retseptor oksitotsina (OXTR) igraet vazhnuiu rol' v protsessakh detorozhdeniia, grudnogo vskarmlivaniia i sotsial'nykh vzaimodeĭstviĭ. V poslednie gody poiavilis' dannye v pol'zu togo, chto OXTR sviazan s razvitiem i progressirovaniem raka molochnoĭ zhelezy (RMZh). Odnako mekhanizmy, privodiashchie k izmeneniiu ego ékspressii, diagnosticheskaia ili prognosticheskaia tsennost' retseptora pri RMZh na dannyĭ moment maloizuchenny. Poétomu my postavili tsel' otsenit' uroven' ékspressii OXTR v obraztsakh RMZh (n=107), a takzhe issledovat' vliianie éstradiola na ego ékspressiiu v kletkakh liniĭ MCF-7 i MDA-MB-231. Uroven' ékspressii OXTR byl znachitel'no nizhe v opukholevoĭ tkani molochnoĭ zhelezy, chem v normal'noĭ tkani, vziatoĭ ot togo zhe patsienta. Ékspressiia OXTR zavisela ot statusa i ékspressii éstrogenovogo retseptora (ER): uroven' mRNK OXTR byl dostoverno nizhe v obraztsakh ER-negativnogo RMZh po sravneniiu s obraztsami ER-pozitivnogo RMZh. Ékspressiia OXTR byla nizhe v obraztsakh patsientov s liuminal'nym RMZh pri nizkom znachenii ékspressii ER (0-5 ballov soglasno immunogistokhimicheskomu (IGKh) issledovaniiu, shkala Allred) po sravneniiu s obraztsami s vysokoĭ ékspressieĭ ER. Uroven' mRNK OXTR byl assotsiirovan s urovnem ékspressii HER2: uroven' mRNK OXTR byl znachitel'no povyshen v obraztsakh liuminal'nogo RMZh s urovnem ékspressii HER2 1 ball, soglasno IGKh issledovaniiu, po sravneniiu s opukholiami s vysokoĭ ékspressieĭ HER2 (2-3 balla). My takzhe pokazali, chto pod deĭstviem éstradiola uvelichivalsia uroven' mRNK OXTR v kletkakh MCF-7, no ne v ER-negativnykh kletkakh MDA-MB-231. Poluchennye dannye ukazyvaiut na to, chto izmenenie ékspressii OXTR v tkaniakh RMZh mozhet byt' vyzvano usileniem ékspressii ER. Sviazi OXTR so statusom T ili N opukholi i ékspressieĭ progesteronovogo retseptora vyiavleno ne bylo.

Topics: Breast Neoplasms; Female; Humans; Oxytocin; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Oxytocin

Modifications of oxytocin (OT) concentration and OT receptor (OXTR) expression level have different effects on breast cancer-derived cells. This study was conducted to evaluate OT variation in breast cancer patients and to evaluate OXTR expression changes in breast cancer tissues.. The plasma concentrations of OT in both breast cancer patients and healthy individuals' samples were assessed. OXTR variations were then assessed in both cancerous and noncancerous breast tissues.. OT had an increase in breast cancer patients and expression of OXTR in contralateral breast was more than cancerous tissues.. Despite the high levels of OT concentration in breast cancer patients, it seems that a lower expression of OXTR in cancerous tissues can be effective in the breast cancer progression.

Topics: Adult; Aged; Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Oxytocin; Receptors, Oxytocin; Transcriptome

The oxytocin receptor, a class A G protein coupled receptor (GPCR), is essentially involved in the physiology of reproduction. Two parameters are crucially important to support high-affinity agonist binding of the receptor: Mg

Topics: Allosteric Regulation; Amino Acid Sequence; Breast Neoplasms; Calcium; Cell Line, Tumor; Cell Membrane; Cholesterol; Dose-Response Relationship, Drug; Female; Fluorescent Dyes; HEK293 Cells; Humans; Mutagenesis, Site-Directed; Oxytocin; Potassium Chloride; Protein Binding; Receptors, Oxytocin; Recombinant Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Sodium Chloride

Oxytocin (OT) has the suppressive effects on breast tumor formation and development. We hypothesized that OT through the NF-κB inhibition can induce the miR-195 up-regulation which it can promote the cell apoptosis and inhibit the cell proliferation. Thirty-two BALB/c female mice were equally divided into four groups to study the effects of OT and atosiban (ATO) (an oxytocin receptor antagonist) on the mammary tumor growth. The animal weight, OT plasma concentration, and the tumor weight and volume were measured. Moreover, the tumor-related signaling pathways including NF-κB, miR-195, and Cyclin D1 were evaluated by qPCR assays, and Akt and ERK proteins were assessed by western blot at the end of the study. The volume and weight of tumors were significantly decreased after OT administration. The phosphorylated Akt and ERK expressions were significantly decreased in the OT group compared to the tumor group. In contrast, the dephosphorylated Akt and ERK expressions were significantly increased in the OT group in comparison with the tumor group. The mRNA expressions of miR-195, OTR, and Bax genes were significantly increased, and the mRNA expression of ERα, PI3K, NF-κB, cyclin D1 and Bcl-2 genes were decreased in the OT group in comparison with the tumor group. Interestingly, ATO administration reversed these effects. These results can exhibit a new therapeutic potential for OT on the down-regulation of the NF-κB and up-regulation of miR-195 and consequently, decrease of the tumor volume and weight in a mouse model of breast cancer.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Proliferation; Disease Models, Animal; Female; Mice; Mice, Inbred BALB C; MicroRNAs; NF-kappa B; Oxytocin; Signal Transduction

Previous studies showed that women with breast cancer treated in anthroposophic clinic versus conventional care had increased quality of life (QoL) parameters, fighting spirit, and anxiety coping. We have now analyzed immune and QoL factors in these 2 groups for possible differences during the first 6 months after admission, prompted by anthroposophic studies, including mistletoe extracts, showing beneficial immune system effects.. Fourteen immunological variables, including leukocyte count, lymphocyte count, activated T cells (CD4+ and CD8+), NK cells, B cells, IL1β, IL6, IL10, and oxytocin, were longitudinally analyzed in both groups (n = 2 × 26). A panel of QoL parameters were analyzed using 3 different instruments. Statistical evaluation included that each patient was its own control.. Cytotoxic CD8+ T cell frequency (percent of lymphocytes analyzed by flow-cytometry) significantly decreased over time in the anthroposophic group versus the conventional group (repeated measures ANOVA, p = 0.05). No major differences were observed in other immunological parameters, whereas QoL variables, anxiety decreased and physical symptoms increased/improved significantly in the anthroposophic group (p = 0.04 and p = 0.05, respectively).. Overall, women with breast cancer in anthroposophic or conventional therapy did not differ in their immune profiles over time, with exception of decreased cytotoxic T cells in the anthroposophic group. Improvement in physical symptoms along with less anxiety in this group may have influenced the brain-immune axis resulting in lower frequency of CD8+ T cells, a feature associated with less aggressive cancer stages. To evaluate whether this observation is associated with good or bad prognosis, further detailed analyses of memory and naïve CD8+ T cells at tumor site and in blood circulation are essential.

Topics: Anxiety; Breast Neoplasms; Cell Count; Complementary Therapies; Cytokines; Female; Humans; Oxytocin; Quality of Life

Women's health is seriously impacted by sexual dysfunction, mental depression, breast cancer, and gynecological cancers. Breast feeding has been found to reduce the risk of in-situ cervical cancer, endometrial cancer of the uterus, ovarian cancer, and breast cancer. This protective effect of breast feeding supports the notion that another functional use of the breast, sexual breast stimulation, promoted by women to incite their sexual arousal and orgasm, is a practice which also reduces the risk of these same cancers, and protects against sexual dysfunction and mental depression. The significance of the practice of breast sex or "sexual breast love" lies with its deeply rooted past in the founding of our species, Homo sapiens. No other species exhibits breast sex, a human cultural activity that is implicated in women's desire, sexual satisfaction, and the development of human sociality. For species females as a whole, nipple stimulation by a partner during sex, over the adult life of a female, has occurred since the inception of H. sapiens, so that the failure to engage in this activity is counter to a species typical practice and endangers women's health. Breast sex results in nipple erection, and may micmic the effects of breast feeding, causing an increase of oxytocin in the body. Breast sex is an enriched type of sexuality that enables love between the sexes and the pair bond. The intimacy of breast sex creates a common ground of sexual knowledge, allowing empathy, cooperation, commitment, and communication. It induces reciprocity and therefore happiness. With breast sex, there is an increase of the positive emotions over the chimpanzees, promoting advanced cognition. Research into whether oxytocin release is caused by stimulation of the breasts in non-lactating women is inconclusive, but cultural studies demonstrate that breast stimulation induces sexual arousal, and research has shown that sexual arousal is associated with oxytocin release.

Topics: Animals; Anthropology; Breast Feeding; Breast Neoplasms; Female; Humans; Male; Oxytocin; Pan troglodytes; Sexual Behavior; Sexual Dysfunctions, Psychological; Sexual Partners; Sexuality; Uterine Contraction; Uterus; Women's Health

Topics: Adult; Breast; Breast Neoplasms; Causality; Cesarean Section; Disease Progression; Female; Humans; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Oxytocin; Retrospective Studies; Risk Factors; Turkey; Women's Health

The high rate of interval malignancies urges for new screening methods for women at high risk for breast cancer. Nipple aspiration provides direct access to the breast tissue and its DNA, and therefore is a likely candidate, but clinical applications have been limited by the failure to obtain nipple aspiration fluid from most women. We performed oxytocin-assisted nipple aspiration in 90 women at increased risk for breast cancer based on family history or genetic test results (n = 63) and/or previous breast cancer (n = 34). Nipple fluid was obtained from 81/90 women (90%) and bilaterally in 77%. Mean discomfort rating was 0.6 (on a 0-10 scale), which was significantly lower than for mammography or MRI. These findings suggest that a new tool for biomarker detection in oxytocin-assisted nipple fluid of women at high risk for breast cancer is at hand.

Topics: Adult; Aged; Breast Neoplasms; Female; Genetic Predisposition to Disease; Humans; Middle Aged; Nipple Aspirate Fluid; Oxytocics; Oxytocin; Risk Factors

Topics: Attitude of Health Personnel; Birth Injuries; Breast Neoplasms; Cesarean Section; Female; Gynecology; Humans; Infant, Newborn; Liability, Legal; Obstetric Labor Complications; Obstetrics; Oxytocics; Oxytocin; Pregnancy; United States

The present study describes the experimental synthetic procedure and the characterization of a new polyaspartamide macromolecular prodrug of paclitaxel, bearing oxytocin residues as targeting moieties. In vitro stability studies of bioconjugate, performed in media mimicking biological fluids (buffer solutions at pH 7.4 and 5.5) and in human plasma, evidenced the high stability of the targeting portion (oxytocin)-polymer linkage and the ability of this conjugate to release linked paclitaxel in a prolonged way in plasma. Moreover, preliminary in vitro antiproliferative studies, carried out on MCF-7 cells, that are oxytocin receptor positive cells, showed that the polymeric conjugate has the same cell growing inhibition ability of free drug.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Chemistry, Pharmaceutical; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Drug Stability; Female; Humans; Hydrogen-Ion Concentration; Hydrolysis; Molecular Structure; Oxytocin; Paclitaxel; Peptides; Polyethylene Glycols; Prodrugs; Receptors, Oxytocin; Solubility; Time Factors

Topics: Adolescent; Adult; Biopsy, Needle; Bodily Secretions; Breast; Breast Neoplasms; DNA; Epithelial Cells; Female; Humans; Middle Aged; Nipples; Oxytocin

The role of the neurohypophyseal peptide oxytocin (OT) and its receptor (OTR) in the breast has been described mainly in relation to breast feeding or to neoplastic growth regulation. We demonstrate here the presence of OT synthesis within the breast under both physiological and neoplastic conditions. In order to clarify whether normal epithelial and myoepithelial cells could synthesize OT, the two different cell types were separated using immunomagnetic technique after enzymatic digestion of breast specimens obtained during reductive mastoplasty. The freshly isolated cells as well as primary stabilized cultures derived from purified normal breast epithelial and myopithelial cells were then studied. Both epithelial and myoepithelial cells contained the mRNA for OT and OTR; however, only myoepithelial cells showed an effective OT synthesis and detectable peptide release in the culture medium. Moreover, OT expression was studied at mRNA and protein level in 10 human breast carcinoma cell lines. OT mRNA was present in half (5 out of 10) of the breast carcinoma cell lines tested, and OT was synthesized and released in the cell medium, irrespective of the estrogen receptor status of the different cell lines. However, in the two ER+ cell lines actively producing OT, such synthesis was significantly increased following estradiol (E2) treatment. These data altogether suggest the existence of a local OT source within the normal as well as within the neoplastic breast, and that such synthesis can be modulated by E2.

Topics: Breast; Breast Neoplasms; Cell Line, Tumor; DNA Primers; Female; Humans; Kinetics; Oxytocin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The present study was designed to determine the short-term effects of alcohol consumption on hormonal responses and mood states in nulliparous women who have regular menstrual cycles. To this aim, we conducted a within-subjects design study in which eight women consumed a 0.4-g/kg dose of alcohol in orange juice during one test session (alcohol condition) and an equal volume of orange juice (control condition) during the other. Changes in plasma prolactin, oxytocin and cortisol levels, blood alcohol concentrations (BACs), and mood states were compared. BAC peaked at approximately 36.7+5.4 min after the consumption of the alcoholic beverage and decreased thereafter. Alcohol consumption significantly increased the area under the concentration-time curve (AUC) of prolactin (P<.01) and decreased the oxytocin AUC (P=.04) when compared to the control condition. Cortisol AUCs were not different across the two experimental conditions. Similar to that previously observed in lactating women, changes in prolactin and oxytocin paralleled changes in feelings of drunkenness. The magnitude and persistence of the alcohol-induced hormonal changes in nulliparous women were significantly less pronounced than those observed in lactating women, further highlighting the dynamics of the system under study during lactation.

Topics: Adult; Affect; Breast Neoplasms; Ethanol; Female; Humans; Hydrocortisone; Lactation; Oxytocin; Prolactin

Oxytocin either increases or inhibits cell growth in different cell subtypes. We tested here the effect of oxytocin on cell proliferation and migration of human dermal microvascular endothelial cells (HMEC) and tumor-associated endothelial cells purified from human breast carcinomas (B-TEC). Oxytocin receptors were expressed in both cell subtypes at mRNA and protein levels. Through oxytocin receptor, oxytocin (1 nmol/L-1 mumol/L) significantly increased cell proliferation and migration in both HMEC and B-TEC, and addition of a selective oxytocin antagonist fully reverted these effects. To verify whether a different expression of adhesion molecule-related genes could be responsible for the oxytocin-induced cell migration, untreated and treated cells were compared applying a microarray technique. In HMEC, oxytocin induced the overexpression of the matrix metalloproteinase (MMP)-17, cathepsin D, and integrin beta(6) genes. In B-TEC, oxytocin significantly switched on the gene profile of some MMP (MMP-11 and MMP-26) and of integrin beta(6). The up-regulation of the integrin beta(6) gene could be involved in the oxytocin-induced cell growth, because this subunit is known to determine activation of mitogen-activated protein kinase-extracellular signal-regulated kinase 2, which is involved in the oxytocin mitogenic effect. In B-TEC, oxytocin also increased the expression of caveolin-1 at gene and protein levels. Because oxytocin receptor localization within caveolin-1-enriched membrane domains is necessary for activation of the proliferative (instead of the inhibitory) response to oxytocin, its enhanced expression can be involved in the oxytocin-induced B-TEC growth as well. Altogether, these data indicate that oxytocin contributes to cell motility and growth in HMEC and B-TEC.

Topics: Breast Neoplasms; Calcium; Cathepsin D; Caveolin 1; Cell Adhesion Molecules; Cell Movement; Cell Proliferation; Endothelial Cells; Endothelium, Vascular; Fluorescent Antibody Technique; Humans; Integrin beta Chains; Matrix Metalloproteinases; Oligonucleotide Array Sequence Analysis; Oxytocin; Receptors, Oxytocin; Reverse Transcriptase Polymerase Chain Reaction; Skin

Sodium/iodide symporter (NIS) expression has recently been described in human breast cancer, with emphasis on its potential exploitation for the treatment of these tumors with radioiodine. In this study, we analyzed the regulation of NIS expression and function in the MCF-7 human breast cancer cell line. Cell exposure to insulin, IGF-I, IGF-II, or prolactin induced significant increases in 125I uptake and the expression of both NIS mRNA and NIS protein. The latter increases were evident after 6 and 12 h of hormonal stimulation, respectively. In immunocytochemistry studies, NIS was detected mainly in the plasma membrane of MCF-7 cells. A low but significant increase in iodide uptake was produced by treatment with activators of the adenylyl cyclase (cAMP) or protein kinase C pathways. Our study demonstrates that: 1) MCF-7 breast cancer cells are capable of active iodide transport that can be stimulated by insulin, IGF-I, IGF-II, or prolactin; 2) both NIS transcript and protein are expressed in these cells, and this expression is also hormonally stimulated; and 3) MCF-7 iodide transport and NIS expression may be influenced by the activation of cAMP or protein kinase C-dependent signaling. These findings increase our understanding of the molecular mechanisms that regulate NIS expression in breast cancer cells, information that is fundamental for future research aimed at the development of targeted radioiodide treatment for this type of cancer.

Topics: Breast Neoplasms; Cell Line, Tumor; Colforsin; Estradiol; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Iodides; Oxytocin; Prolactin; Symporters

Transcriptional activation of the gene coding for the neuropeptide hormone oxytocin by oestrogens does not follow the classical model of oestrogen receptor action. The oxytocin promoter does not contain an oestrogen response element (ERE), but instead a high-affinity binding site for nuclear orphan receptors. In the present study, the oestrogen-dependent up-regulation of the bovine oxytocin promoter is investigated in MDA-MB 231 cells. Control by oestrogen is shown to be dependent on the integrity of the nuclear orphan receptor binding site and the presence of ligand-activated oestrogen receptor, but independent of oestrogen receptor binding to DNA. Partial agonists tamoxifen and raloxifen and the pure antagonist ICI 182 780 all show agonistic activities on transcription, while exhibiting normal binding affinities to oestrogen receptor (ER)alpha. Nuclear orphan receptors oestrogen receptor-related receptor alpha (ERRalpha) and germ cell nuclear factor (GCNF) are expressed to significant levels in MDA-MB 231 cells. Binding of ERRalpha to the oxytocin promoter binding site can be demonstrated, suggesting the involvement of this nuclear orphan receptor in oestrogen-dependent up-regulation. The oestrogenic stimulation of the oxytocin promoter apparently is dependent on the stimulation of the transcriptional activity of this nuclear orphan receptor by ERK-1/ERK-2 mitogen-activated protein kinases (MAP kinases). This novel nonclassical mechanism of oestrogen action most probably is not restricted to the regulation of neuropeptide hormone expression, but may further contribute to the multitude of tissue-specific effects of oestrogenic substances.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Cattle; Cell Line, Tumor; Epithelial Cells; ERRalpha Estrogen-Related Receptor; Estrogen Antagonists; Estrogens; Gene Expression Regulation; Humans; Oxytocin; Receptors, Cytoplasmic and Nuclear; Receptors, Estrogen; Response Elements; Signal Transduction; Transcriptional Activation; Up-Regulation

Oxytocin receptors (OTR) have been described in a number of tumours of different origin, and represent a new target for specific radiolabelled oxytocin (OT) analogues in cancer diagnosis and therapy. By linking the DOTA chelating agent to position 8 of the deamino derivative of Lys(8)-vasotocin (dLVT), we obtained a new compound (DOTA-dLVT) with the following characteristics: (1) it forms a monomeric and stable compound that binds to OTR with an affinity comparable to that of the endogenous OT ligand; (2) it is characterised by a very good selectivity profile for the human OTR, with a low affinity binding to the closely related V1a, V1b and V2 vasopressin receptor subtypes; (3) it induces rapid and persistent receptor internalisation and (4) when radiolabelled, [(111)In]-DOTA-dLVT is efficiently and selectively taken up by OTR-positive tumours grown in mice. These features makes radiolabelled DOTA-dLVT a very good candidate for the radiotargeting of OTR-expressing tumours.

Topics: Animals; Breast Neoplasms; Carcinoma; Chelating Agents; COS Cells; Glioblastoma; Heterocyclic Compounds, 1-Ring; Humans; Indium Radioisotopes; Isotope Labeling; Mice; Neoplasms; Oxytocin; Protein Binding; Radioactive Tracers; Radioligand Assay; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Oxytocin; Sensitivity and Specificity; Stomach Neoplasms; Tissue Distribution; Transfection; Tumor Cells, Cultured; Vasotocin

Oxytocin (OT) inhibits the proliferation of MCF7 estrogen-dependent human breast cancer cells, via specific OT receptors (OTR). Besides this effect, we report that OT modulates the expression of estrogen receptor alpha (ERalpha) in MCF7 cells, both at mRNA and protein level. Since the first 24 h of OT treatment the ERalpha mRNA levels are down-regulated; in contrast, ERalpha protein expression decreases at a later time. The reduced number of ERalpha goes in parallel to a temporary increase in the binding affinity of these receptors as well as to a significant increase in their estradiol (E2)-induced transcription activity. The increase in both binding affinity and transcriptional activity of ERalpha likely balances the reduction in the number of ERalpha binding sites, ruling out the hypothesis that part of the OT contrasting effect on E2-induced cell proliferation could depend on the reduced E2 binding to MCF7 cells and supporting the hypothesis of an exclusively direct OT-antimitogenic effect. This is the first evidence that OT modulates the expression of ERalpha receptors in human neoplastic cells.

Topics: Breast Neoplasms; Cell Division; Cytoplasm; Estradiol; Estrogen Receptor alpha; Gene Expression Regulation, Neoplastic; Humans; Neoplasms, Hormone-Dependent; Oxytocin; Protein Binding; Receptors, Estrogen; Receptors, Progesterone; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Transcription, Genetic; Transfection; Tumor Cells, Cultured

A 41-year-old woman with breast cancer was referred to the pain management clinic for a course of acupuncture for intense pain following a subcutaneous mastectomy and a latissimus dorsi flap reconstruction. She was treated with a standard course of acupuncture for breast pain, using paravertebral segmental points, trigger points, plus contralateral L14 on the non-lymphoedematous arm. She experienced an episode of galactorrhoea six days following the first treatment and during the second treatment. She had not previously lactated for four years. CT and MRI of the brain revealed no focal abnormality. Acupuncture has been used in to promote lactation in the Traditional Chinese literature using the 'Tianzong' acupoint SI11. This acupoint coincided with a trigger point over infraspinatus that was included in the neurophysiologically based acupuncture treatment. Quantitative analysis has shown an increase in the production of prolactin and oxytocin following acupuncture. These hormones are involved in the synthesis and release of milk from mammary glands respectively. This is the first report of galactorrhoea, in the contralateral normal breast, following acupuncture in a patient with breast cancer.

Topics: Acupuncture Therapy; Adult; Axilla; Breast Neoplasms; Female; Galactorrhea; Humans; Oxytocin; Pain; Pain Management; Prolactin

The sodium/iodide symporter (NIS) stimulates iodide uptake in normal lactating breast, but is not known to be active in nonlactating breast or breast cancer. We studied NIS gene regulation and iodide uptake in MCF-7 cells, an estrogen receptor (ER)-positive human breast cancer cell line. All-trans retinoic acid (tRA) treatment stimulated iodide uptake in a time- and dose-dependent fashion up to approximately 9.4-fold above baseline. Stimulation with selective retinoid compounds indicated that the induction of iodide uptake was mediated by retinoic acid receptor. Treatment with tRA markedly stimulated NIS mRNA and immunoreactive protein ( approximately 68 kDa). tRA stimulated NIS gene transcription approximately 4-fold, as shown by nuclear run-on assay. No induction of iodide uptake was observed with RA treatment of an ER-negative human breast cancer cell line, MDA-MB 231, or a normal human breast cell line, MCF-12A. The iodide efflux rate of tRA-treated MCF-7 cells was slow (t(1/2) = 24 min), compared with that in FRTL-5 thyroid cells (t(1/2) = 3.9 min), favoring iodide retention in MCF-7 cells. An in vitro clonogenic assay demonstrated selective cytotoxicity with (131)I after tRA stimulation of MCF-7 cells. tRA up-regulates NIS gene expression and iodide uptake in an ER-positive breast cancer cell line. Stimulation of radioiodide uptake after systemic retinoid treatment may be useful for diagnosis and treatment of some differentiated breast cancers.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Breast Neoplasms; Carrier Proteins; Cell Line; Colforsin; Down-Regulation; Female; Humans; Iodides; Iodine Radioisotopes; Kinetics; Membrane Proteins; Oxytocin; Prolactin; Rats; Sodium Iodide; Symporters; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured

Oxytocin (OT) receptors (OTRs) have been demonstrated in a number of human breast tumors and tumor cells, but it was not clear whether the receptors were functional. We examined the regulation and function of OTR in a tumor cell line, Hs578T, derived from human breast. These cells expressed moderate levels of OTR when cultured in 10% FBS, as demonstrated by RT-PCR and binding analyses. Serum deprivation resulted in the loss of OTRs, with no effect on cell viability. Restoration of serum and addition of 1 microM dexamethasone (DEX) increased OTR levels by about 9-fold. Up-regulation was blocked by the addition of phospholipase C and PKC inhibitors. Serum/DEX treatment also increased steady state OTR messenger RNA levels. OT increased intracellular Ca2+ in a time- and dose-responsive manner, and the effects of OT were lost when OTRs were down-regulated by serum starvation. Serum/DEX up-regulation of OTR restored the responsiveness to OT. OT also stimulated ERK-2 (extracellular signal-regulated protein kinase) phosphorylation and PGE2 synthesis in Hs578T cells. In addition to showing that OTRs in the breast tumor cells are functional, these studies show that Hs578T cells can be used to study molecular regulation of OTR gene expression and intracellular signaling pathways stimulated by OT.

Topics: Blood; Breast Neoplasms; Calcium; Carcinosarcoma; Dexamethasone; Dinoprostone; Female; Gene Expression Regulation; Glucocorticoids; Humans; Mitogen-Activated Protein Kinase 1; Oxytocin; Phosphorylation; Protein Kinase C; Receptors, Oxytocin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Tumor Cells, Cultured

Research suggests that oxytocin acts as a growth modulating agent for breast cancer cells. However, the signaling mechanisms responsible for these modulatory effects have not been fully elucidated. In the physiological setting oxytocin is known to stimulate contraction of myometrial cells in the uterus and myoepithelial cells in the breast by increasing intracellular free calcium ([Ca2+]i). The expression of oxytocin receptor mRNA in T-47D breast cancer cells, and four additional breast cancer cell lines (BT-549, MCF-7, MDA-MB- 231, ZR-75-1), was confirmed by RT-PCR analysis. Oxytocin-induced changes in [Ca2+]i in indo-1 AM loaded T-47D breast cancer cells were monitored using flow cytometric analysis. In this cell line, oxytocin (0, 1, 10, 100, and 1,000 nM) did not induce a dose-dependent increase in the mean 405 nm/485 nm emission ratio. These results indicate that oxytocin signaling in T-47D breast cancer cells does not appear to involve an increase in [Ca2+]i.

Topics: Base Sequence; Breast Neoplasms; Calcium; DNA Primers; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Oxytocin; Receptors, Oxytocin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Oxytocin (OT) inhibits the proliferation of breast-cancer cells in vitro via a specific G-coupled receptor. To elucidate the intracellular mechanism involved in this biological effect, different G-coupled receptor mediators have been investigated in untreated and OT-treated MDA-MB231 breast-carcinoma cells. In these cells, after OT treatment, a significant cAMP increase was observed using a radioimmunoassay procedure, whereas the Ca2+ (determined with the fluorescent probe fura-2) and the inositol phosphate (determined after cell labeling with myo(2-(3)H)-inositol) concentrations were not modified, contrary to what has been observed in myometrial and myo-epithelial cells. The PKA inhibitor PKI (6-22) amide reverted the effect of OT, indicating that the anti-proliferative effect of the peptide is strictly related to the cAMP-PKA pathway. OT treatment did not modify tyrosine phosphorylation either. Our results indicate that in breast epithelial cells devoid of contractile activity, cAMP is the intracellular mediator of OT action, whereas the Ca2+-phosphoinositide system is not involved.

Topics: Breast Neoplasms; Cell Division; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Female; Humans; Oxytocin; Signal Transduction; Tumor Cells, Cultured

Immunohistochemical analysis for products of vasopressin and oxytocin gene expression was performed on acetone-fixed tissues from 19 breast cancers representing a variety of tumor sub-types. Studies employed the avidin-biotin complex (ABC) immunohistochemical procedure and utilized rabbit polyclonal antibodies to arginine vasopressin (VP), provasopressin (ProVP), vasopressin-associated human glycopeptide (VAG), oxytocin (OT), oxytocin-associated human neurophysin (OT-HNP), and a mouse monoclonal antibody to vasopressin-associated human neurophysin (VP-HNP). Western Blot analysis was performed on protein extracts of fresh-frozen tissues from 12 additional breast tumors. While VP gene related proteins were not detected in normal breast tissue, immunohistochemistry revealed the presence of VP, ProVP, and VAG in all neoplastic cells for all of the tumor tissues examined. Vasopressin-associated human neurophysin was evident in only one of 19 acetone-fixed tumor preparations. However, Western blot analysis for all 12 fresh-frozen tumor samples showed the presence of two proteins, 42,000 and 20,000 daltons, that were immunoreactive with antibodies to VP, VP-HNP, and VAG. Oxytocin and OT-HNP, by immunohistochemistry, were found to be common to cells of normal breast tissues. For tumors, positive staining for OT was observed in 8 of 18 tumors, while OT-HNP was not detected in any of the tumors examined. These findings indicate that VP gene expression is a selective feature of all breast cancers, and that products of this expression might therefore be useful as markers for early detection of this disease and as possible targets for immunotherapy.

Topics: Antibodies, Monoclonal; Arginine Vasopressin; Biomarkers, Tumor; Blotting, Western; Breast Neoplasms; Female; Glycopeptides; Humans; Immunohistochemistry; Neurophysins; Oxytocin; Protein Precursors; Vasopressins

This hypothesis proposes that carcinogens in the breast are generated by the action of superoxide free radicals released when acinal gland distension, under the influence of unopposed prolactin, causes microvessel ischaemia. Inadequate nipple care in the at-risk years leads to ductal obstruction preventing the elimination of carcinogens from the breast. The regular production of oxytocin (OT) from nipple stimulation would cause contraction of the myoepithelial cells, relieving acinal gland distension and aiding the active elimination of carcinogenic fluid from the breast. Mechanical breast pump stimulation causes an increase in plasma OT levels in the luteal but not in the follicular phase of the menstrual cycle. OT production upon nipple stimulation in the luteal phase of premenopausal, non-lactating women may be protective against the high rates of mitotic breast cell division noted at this time via the potential to block the effect of oestrogen. The epidemiology of breast cancer suggests that lengthy lactation time is beneficial. Sexual activity in nulliparous women also protects and OT levels have been shown to rise with orgasm in women and in men. OT systems in the brain are intricately linked to oestrogen and progesterone levels, and it is possible that these hormones may modify the OT secretory response both centrally and through an effect on the sensitivity of the breast. OT production with nipple care and in sex and lactation, and the reduction in cycling ovarian hormones that occurs with pregnancy, may all be important preventative factors in the development of breast cancer both pre- and post-menopausally.

Topics: Breast Neoplasms; Female; Humans; Ischemia; Lactation; Menstrual Cycle; Microcirculation; Models, Biological; Nipples; Oxytocin; Prolactin; Sex; Superoxides

Topics: Breast Neoplasms; Cell Division; Female; Hormone Antagonists; Humans; Oxytocin; Receptors, Oxytocin; RNA, Messenger; Tumor Cells, Cultured; Vasotocin

In this study we show that treatment of MDA-MB231 hormone-independent human breast cancer cells with oxytocin (OT) or with the OT analogue F314 induces significant growth inhibition together with a change in cell phenotype. In MCF7 and T47D human breast cancer cells, OT inhibits oestrogen-induced cell growth. In these same cells, OT administration significantly enhances the inhibitory effect of tamoxifen on cell proliferation. MDA-MB231, MCF7 and T47D cells all express mRNA specific for the OT receptor. These data suggest that it may be possible to inhibit breast cancer growth using OT and OT analogues.

Topics: Breast Neoplasms; Cell Division; Fluorescent Antibody Technique; Humans; Oxytocin; Polymerase Chain Reaction; Receptors, Oxytocin; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured

In order to isolate and characterize genes whose expression may be altered in breast malignancy, we screened a cDNA library with a polyclonal anti-serum against breast-cancer-metastasis membranes and isolated several immunopositive clones. One of these, AJ1, was analyzed in detail and found to be expressed at varying levels as a 3.3-kb mRNA in all of 143 breast cancers. High expression was associated with lymph-node involvement (p = 0.03). Comparison between high- and low-expressing groups showed a significant difference at 4 and 6 years for both overall (p = 0.004 and p = 0.002 respectively) and disease-free (p = 0.0001 and p = 0.04 respectively) survival, but not at 11 years. AJ1 was expressed at much lower levels in non-malignant biopsies as compared with malignant tissue (p = 0.001). Expression was observed in breast-cancer cell lines MCF-7, ZR-75-1, T47D, MDA-MB-231 and HBL 100. Partial sequence analysis of the 620 bp clone showed complete homology with human heat-shock protein 89 alpha. In addition to being heat-inducible in all the breast cell lines examined, AJ1 levels were increased by estradiol (blocked by cyclohexamide and tamoxifen), EGF, oxytocin and vasopressin in a time-dependent manner in MCF-7 cells and by estradiol, EGF, prolactin and hydrocortisone in T47D cells. In MDA-MB-231 cells, EGF caused down-regulation of AJ1 mRNA levels. The increasing evidence for the association of heat-shock proteins with steroid receptors suggests that AJ1 may play an important role in the control of estrogen-receptor transcriptional activity in breast cancers.

Topics: Blotting, Northern; Breast Neoplasms; Epidermal Growth Factor; Estradiol; Gene Expression; Gene Expression Regulation, Neoplastic; Heat-Shock Proteins; Humans; Hydrocortisone; Oxytocin; Prolactin; RNA, Messenger; RNA, Neoplasm; Tamoxifen; Tumor Cells, Cultured; Vasopressins

DNA sequences in the 5'-flanking region of rat and bovine oxytocin genes were examined for their capacity to confer estrogen responsiveness to their homologous promoters. In contrast to the 5'-flanking region of the rat oxytocin gene, upstream promoter sequences up to 3200 bp of the bovine gene linked to the chloramphenicol acetyltransferase (CAT) reporter gene which were transfected in estrogen receptor expressing MCF-7 cells did not respond to estrogen. Testing 5'-deletion mutants of the rat upstream region linked to the luciferase gene in P19 embryocarcinoma cells co-transfected with an estrogen receptor expression plasmid showed that two regions each associated with approximately 15-fold stimulation of promoter activity were located between nucleotides -172 and -149 and between -148 and +16 in the rat gene. The former region contains the imperfect palindrome GGTGACCTTGACC which differs in one nucleotide from the estrogen response element (ERE) consensus. It is concluded that the corresponding motive CATAACCTTGACC of the bovine gene is not a functional ERE. Thus, the estrogen responsiveness of oxytocin genes is species-dependent.

Topics: Animals; Base Sequence; Breast Neoplasms; Cattle; Cell Line; Chloramphenicol O-Acetyltransferase; Estradiol; Female; Humans; Molecular Sequence Data; Oxytocin; Plasmids; Promoter Regions, Genetic; Rats; Recombinant Fusion Proteins; Sequence Homology, Nucleic Acid; Teratoma; Transfection

The arginine vasopressin and oxytocin content of normal and cancerous human breast tissue were measured using radioimmunoassay. Both peptides were present in amounts greater than that found in the circulation, but no difference between normal and malignant tissues was found. Binding of [3H]oxytocin and [3H]vasopressin were characterized in human breast carcinoma cells (MCF7 cells). Binding of both hormones to MCF7 cells was specific and saturable, the vasopressin receptor found to be of the V1 subtype. Scatchard analyses of the data were linear, indicating a single high affinity, low capacity binding site for each hormone (vasopressin: KD = 47.4 +/- 1.6 nmol/liter, Bmax = 27,300 +/- 6,500 sites/cell; oxytocin: KD = 51.3 +/- 0.4 nmol/liter, Bmax = 87,000 +/- 4,000 sites/cell). The effects of vasopressin and oxytocin on the growth of MCF7 cells were assessed using protein accumulation and cell numbers. Vasopressin at 10-1000 pmol/liter was mitogenic for MCF7 cells, but higher doses (10 nmol/liter) were growth inhibitory. Oxytocin was also mitogenic for MCF7 cells but to a lesser extent than vasopressin. In conclusion, we suggest that vasopressin and possibly oxytocin may be important modulators of the growth of some human breast carcinomas.

Topics: Arginine Vasopressin; Binding, Competitive; Breast; Breast Neoplasms; Cell Line; Female; Humans; Inositol Phosphates; Kinetics; Oxytocin; Radioimmunoassay; Receptors, Angiotensin; Receptors, Oxytocin; Receptors, Vasopressin; Reference Values; Vasopressins

Topics: Anabolic Agents; Breast Neoplasms; Dihydrotestosterone; Gastrointestinal Diseases; Humans; Neoplasms; Oxytocin; Steroids; Toxicology