8-hydroxy-2--deoxyguanosine and Breast-Neoplasms

Oxidative stress may play an important role in both initiation and progression of breast cancer. We conducted the first systematic epidemiologic review to summarize the published literature on oxidative stress biomarkers and breast cancer.. We implemented systematic search strategies to identify published studies of oxidative stress biomarkers and (1) risk of developing breast cancer and (2) breast cancer prognosis using the PRISMA statement guidelines.. We identified eleven case-control studies of oxidative stress biomarkers and breast cancer. Biomarkers utilized varied and menopausal status was a key modifying factor. Across three nested case-control studies with biomarkers measured before diagnosis, one reported increased risk of postmenopausal breast cancer in association with 8-oxodG (DNA damage biomarker), while two (one of F. DNA damage may increase risk of breast cancer among postmenopausal women, while lipid peroxidation may be inversely associated with premenopausal breast cancer. Lipid peroxidation may be associated with survival after breast cancer diagnosis; however, results require evaluation in large, prospective cohort studies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers, Tumor; Breast Neoplasms; Deoxyguanosine; Female; Humans; Middle Aged; Oxidative Stress; Prognosis; Risk Factors; Survival Analysis

This post hoc analysis examined cruciferous vegetable intake on urinary oxidative metabolites in postmenopausal women. Intervention participants (n = 69) received cruciferous vegetables (≥14 cups/week) during a 3-week period. First morning urine measured 8-isoprostane and 8-hydroxy-2'-deoxyguanosine. Dietary intake was estimated using 24-h recalls. When stratified by history of breast cancer, those with breast cancer had significantly lower post-intervention urinary 8-hydroxy-2'-deoxyguanosine values in the intervention arm versus. the control arm (1.1 ng/mL vs. 3.2 ng/mL, p = .01) after adjustment for baseline 8-hydroxy-2'-deoxyguanosine. This was not observed in those without breast cancer. Further work is needed to understand the role of breast cancer in these relationships.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers, Tumor; Brassica; Breast Neoplasms; Case-Control Studies; Deoxyguanosine; Diet; Dinoprost; Female; Humans; Middle Aged; Oxidative Stress

Pre-clinical and epidemiologic studies provide rationale for evaluating lipophilic statins for breast cancer prevention. We conducted a single-arm, biomarker modulation trial of lovastatin among women with increased risk of breast cancer. Eligibility criteria included a deleterious germline mutation in BRCA1, BRCA2, CDH1, or TP53; lifetime breast cancer risk of ≥20 % as estimated by the Claus model; or personal history of estrogen receptor and progesterone receptor-negative breast cancer. Participants received 40 mg of lovastatin orally twice daily for 6 months. We evaluated the following biomarkers before and after lovastatin use: breast duct cytology (primary endpoint), serum lipids, C-reactive protein, insulin-like growth factor-1, IGF binding protein-3, lipid peroxidation, oxidative DNA damage, 3-hydroxy-3-methylglutaryl CoA reductase genotype, and mammographic density. Thirty women were enrolled, and 26 (86.7 %) completed the study. For the primary endpoint of changes in breast duct cytology sampled by random periareolar fine needle aspiration, most participants [57.7 %, 95 % confidence interval (CI) 38.9-74.5 %] showed no change after lovastatin; 19.2 % (CI 8.1-38.3 %) had a favorable change in cytology, 7.7 % (95 % CI 1.0-25.3 %) had an unfavorable change, and 15.4 % (95 % CI 5.5-34.2 %) had equivocal results due to acellular specimens, usually after lovastatin. No significant changes were observed in secondary biomarker endpoints. The study was generally well-tolerated: 4 (13.3 %) participants did not complete the study, and one (3.8 %) required a dose reduction. This trial was technically feasible, but demonstrated no significant biomarker modulation; contributing factors may include insufficient sample size, drug dose and/or duration. The results are inconclusive and do not exclude a favorable effect on breast cancer risk.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Anticarcinogenic Agents; Biomarkers, Tumor; Biopsy, Fine-Needle; Breast Density; Breast Neoplasms; C-Reactive Protein; Deoxyguanosine; DNA Damage; Female; Genetic Predisposition to Disease; Humans; Hydroxymethylglutaryl CoA Reductases; Lipid Peroxidation; Lipids; Lovastatin; Mammary Glands, Human; Middle Aged; Oxidative Stress; Patient Compliance

Some experimental evidence suggests that BRCA1 plays a role in repair of oxidative DNA damage. Selenium has anticancer properties that are linked with protection against oxidative stress. To assess whether supplementation of BRCA1 mutation carriers with selenium have a beneficial effect concerning oxidative stress/DNA damage in the present double-blinded placebo control study, we determined 8-oxodG level in cellular DNA and urinary excretion of 8-oxodG and 8-oxoGua in the mutation carriers. We found that 8-oxodG level in leukocytes DNA is significantly higher in BRCA1 mutation carriers. In the distinct subpopulation of BRCA1 mutation carriers without symptoms of cancer who underwent adnexectomy and were supplemented with selenium, the level of 8-oxodG in DNA decreased significantly in comparison with the subgroup without supplementation. Simultaneously in the same group, an increase of urinary 8-oxoGua, the product of base excision repair (hOGG1 glycosylase), was observed. Therefore, it is likely that the selenium supplementation of the patients is responsible for the increase of BER enzymes activities, which in turn may result in reduction of oxidative DNA damage. Importantly, in a double-blinded placebo control prospective study, it was shown that in the same patient groups, reduction in cancer incidents was observed. Altogether, these results suggest that BRCA1 deficiency contributes to 8-oxodG accumulation in cellular DNA, which in turn may be a factor responsible for cancer development in women with mutations, and that the risk to developed breast cancer in BRCA1 mutation carriers may be reduced in selenium-supplemented patients who underwent adnexectomy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adnexal Diseases; BRCA1 Protein; Breast Neoplasms; Case-Control Studies; Chromatography, High Pressure Liquid; Deoxyguanosine; Dietary Supplements; DNA Damage; Double-Blind Method; Female; Humans; Leukocytes; Mutation; Ovarian Neoplasms; Oxidation-Reduction; Oxidative Stress; Placebos; Prognosis; Sodium Selenite; Uric Acid; Vitamins

This study sought to evaluate the relationship between dietary intake of fat, polyunsaturated fat, saturated fat, arachidonic acid, and selected dietary antioxidants and levels of oxidative damage as measured by urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-epi-prostaglandin F2alpha (8-iso-PGF2alpha) in women previously treated for breast cancer. Two hundred two study subjects participating in the Women's Healthy Eating and Living (WHEL) study were included in this ancillary study. Dietary intakes and concentrations of urinary 8-OHdG and 8-iso-PGF2alpha were measured at baseline and 12 mo in the 179 women included in the analytical cohort. Study subjects demonstrated a significant reduction in dietary total, polyunsaturated, and saturated fat intake and a significant increase in vitamins E and C and beta-carotene intake from baseline to 12 mo. Linear mixed-models analysis using baseline and Year 1 data indicated that vitamin E intake was inversely associated with both 8-OHdG and 8-iso-PGF2alpha. 8-Iso-PGF2alpha is increased with increased body mass index (BMI) and polyunsaturated fatty acid (PUFA) intake, indicating an increase in lipid peroxidation with greater BMI and higher PUFA intake. 8-OHdG was inversely related to age but positively related to arachidonic acid, indicating an increase in DNA damage with higher intake of arachidonic acid (meat). The results of this nested case-controlled study provide potential mechanisms by which a high fruit and vegetable, low-fat diet might reduce the recurrence rate of or early-stage breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antioxidants; Biomarkers; Body Mass Index; Breast Neoplasms; Case-Control Studies; Cohort Studies; Deoxyguanosine; Diet; Dietary Fats; Dinoprost; DNA Damage; Fatty Acids, Unsaturated; Female; Humans; Lipid Peroxidation; Middle Aged; Oxidative Stress; Secondary Prevention; Time Factors

While biomarkers have been proposed to identify individuals at risk for radiation-induced cardiovascular disease (RICVD), little is known about long-term associations with cardiac events. We examined associations of biomarkers of oxidative stress (myeloperoxidase, growth differentiation factor-15, 8-hydroxy-2'-deoxyguanosine [8-OH-dG], placental growth factor), cardiac injury (troponin I, cystatin-C), inflammation (interleukin-6, C-reactive protein), and myocardial fibrosis (transforming growth factor-ß) with long-term RICVD in breast cancer (BC) survivors. We conducted a nested case-control study within the Women's Health Initiative of postmenopausal women with incident BC stages I-III, who received radiation and had pre- and post-BC diagnosis serum samples. Cases (n = 55) were defined as developing incident, physician-adjudicated myocardial infarction, coronary heart disease death, other CVD death, heart failure, or stroke after BC. Cases were matched to three controls (n = 158). After adjustment, a higher 8-OH-dG ratio was significantly associated with an elevated long-term risk of RICVD, suggesting oxidative DNA damage may be a putative pathway for RICVD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Breast Neoplasms; Cardiovascular Diseases; Case-Control Studies; Female; Humans; Myocardial Infarction; Oxidative Stress; Placenta Growth Factor; Risk Factors

Triclosan (TCS), a widely prescribed broad-spectrum antibacterial agent, is an endocrine-disrupting chemical. The relationship and biological mechanisms between TCS exposure and breast cancer (BC) are disputed. We aimed to examine the correlation between urinary TCS exposure and BC risk and estimated the mediating effects of oxidative stress and relative telomere length (RTL) in the above association.. This case-control study included 302 BC patients and 302 healthy individuals in Wuhan, China. We detected urinary TCS, three common oxidative stress biomarkers [8-hydroxy-2-deoxyguanosine (8-OHdG), 8-iso-prostaglandin F. Significant associations were observed between log-transformed urinary concentrations of TCS, 8-OHdG, HNE-MA, 8-isoPGF. In conclusion, our study provides epidemiological evidence to confirmed the deleterious effects of TCS on BC and indicated the mediating effect of oxidative stress and RTL on the correlation between TCS and BC risk. Moreover, exploring the contribution of TCS to BC can clarify the biological mechanisms of TCS exposure, provide new clues for the pathogenesis of BC, which is of great significance to improving public health systems.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Breast Neoplasms; Case-Control Studies; Female; Humans; Leukocytes, Mononuclear; Oxidative Stress; Telomere; Triclosan

Oxidative stress combined with nullity of xenobiotic metabolizing GSTT1/GSTM1/CYP2E1 genes may increase the susceptibility of agricultural workers to adverse health effects including cancer. The present study was conducted to determine; the prevalence of polymorphisms in GSTM1, GSTT1 and CYP2E1 genes, serum 8-hydroxy-2'-deoxygunosine levels, and the role of these markers in risk of cancer among agricultural workers occupationally exposed to pesticides.. A total of 360 participants, of which 180 belonging to farming group diagnosed with leukemia (n=60), lymphoma (n=60) and breast cancers (n=60), 90 in non-farming group diagnosed with similar cancers and the other 90 as healthy controls with neither history of occupational exposure nor diagnosed with any type of cancers were recruited. Following the questionnaire survey, serum 8-OHdG and genetic polymorphisms in the three genes were determined using ELISA and PCR methods respectively.. The results of the study revealed that farm workers carrying GSTT1 null genotype had increased risk for lymphoma (OR = 5.34; 95% CI = 1.80-15.82) and breast cancer (OR=4.04; 95% CI = 1.24-13.07). For farm workers carrying GSTM1 null genotype, the risk was six-fold for breast cancer (OR = 6.88; 95% CI =1.88-25.99). Further, there found a significant difference between 8-OHdG and nullity of CYP2E1 among the farm workers diagnosed with leukemia.. The findings of the present study suggest that the polymorphisms in detoxifying genes among farm workers occupationally exposed to pesticides and the oxidative stress may likely be responsible for triggering the mechanism of malignancy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Breast Neoplasms; Cytochrome P-450 CYP2E1; Drug-Related Side Effects and Adverse Reactions; Farmers; Female; Humans; Leukemia; Lymphoma; Pesticides; Polymorphism, Genetic; Xenobiotics

Breast cancer (BC) is one of the most prevalent and reported cancers among Saudi women. Detection of BC in the early invasive stage (stages I, II) has an advantage in treating patients over detection in the late invasive stage (stages III, IV). Tumor markers are used to aid in diagnosis, treatment monitoring, and recurrence detection of malignant tumors. 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a marker of nucleic damage owing to oxidative stress.. We studied the blood levels of 8-OHdG in 50 women with benign breast tumors, 50 women with BC, and 50 healthy women as a control group.. The concentrations of 8-OHdG were significantly increased in the BC group (55.2 ng/dL) compared with the benign tumor group (30.2 ng/dL) and with the healthy control group (9.08 ng/dL). The same pattern was observed with other diagnostic markers, including carcinoembryonic antigen and cancer antigen 15-3. Significant positive correlations between 8-OHdG and both carcinoembryonic antigen (r = 0.63; P < .001) and cancer antigen 15-3 (r = 0.51; P < .001) were noticed. The levels of 8-OHdG were significantly higher in stage I (81 ng/dL) compared with stage II (51 ng/dL; P < .05), stage III (38 ng/dL; P < .01), and stage IV (19 ng/dL; P < .001). In addition, serum 8-OHdG had a high diagnostic performance in BC (area under the curve, 0.86; sensitivity = 82%; specificity = 80% at cutoff value 21.4 ng/mL). 8-OHdG is associated with BC risk according to logistic regression analysis.. We concluded that the significant increase of serum levels of 8-OHdG in patients with BC can be used as a potential noninvasive biomarker for early detection of BC. However, large sample sizes from different stages and types of BC should be included in any future study to confirm the present findings before translating the findings into routine clinical application.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers, Tumor; Breast Neoplasms; Carcinoembryonic Antigen; Case-Control Studies; Early Detection of Cancer; Female; GPI-Linked Proteins; Humans; Mucin-1; Postmenopause; Risk; Sensitivity and Specificity

Oxidative stress has been linked to cancer development in previous studies. However, the association between pre-diagnostic oxidatively generated DNA/RNA damage levels and incident cancer has rarely been investigated. Urinary oxidized guanine/guanosine (OxGua) concentrations, including 8-hydroxy-2'-deoxyguanosine, were assessed in 8,793 older adults in a population-based German cohort. 1,540 incident cancer cases, including 207 lung, 196 colorectal, 218 breast and 245 prostate cancer cases were diagnosed during over 14 years of follow-up. Associations of OxGua levels with cancer outcomes were not observed in the total population in multi-variable adjusted Cox regression models. However, in subgroup analyses, colorectal cancer incidence increased by 8%, 9% and 8% with one standard deviation increase in OxGua levels among current non-smokers, female and non-obese participants, respectively. Additionally, among non-smokers, overall and prostate cancer incidences statistically significantly increased by 5% and 13% per 1 standard deviation increase in OxGua levels, respectively. In contrast, OxGua levels were inversely associated with the risk of prostate cancer among current smokers. However, none of the subgroup analyses had p-values below a threshold for statistical significance after correction for multiple testing. Thus, results need to be validated in further studies. There might be a pattern that oxidatively generated DNA/RNA damage is a weak cancer risk factor in the absence of other strong risk factors, such as smoking, obesity and male sex.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Breast Neoplasms; Colorectal Neoplasms; DNA Damage; Female; Follow-Up Studies; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Obesity; Oxidative Stress; Prostatic Neoplasms; Risk Factors; Sex Factors; Smoking

Breast cancer is the most common neoplasm in women and has the highest associated mortality rate. Rapid detection programmes can provide early diagnosis and increase the chances of survival. There are no specific tumor biomarkers for the early phase of the disease. The primary aim of this study was to search a blood biomarker with levels that exceeded the normal range established in the general population that could be used to screen breast cancer.. Case-control study. Conventional as well as research (NGAL, EGFR and 8-OHdG) tumor biomarkers were analyzed.. A total of 126 women were enrolled (cases: 63 patients with local breast cancer; Controls: 63 healthy women). Significant differences were found in patients with higher levels of the conventional markers, Ca15.3, CEA, Cyfra 21.1 and NSE. However, when commercial cut-off values were used, only Ca 15.13 was significant. In the group of research biomarkers, significantly higher levels of EGFR were found in the control group, and of 8-OHdG in the case group. Using logistic regression analysis and a ROC curve, an equation composed of five markers, Ca 15.3, NSE, NGAL, EGFR and 8-OHdG, which yielded a correct diagnostic probability of breast cancer of 91.8% was obtained.. 8-OHdG has been identified as a new potential marker for screening early stage breast cancer. In addition, a model that combines five blood markers that can be used as a diagnostic test in certain groups of patients has been developed. New studies with a larger sample size are needed to verify the results obtained.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; alpha-Fetoproteins; Antigens, Neoplasm; Biomarkers, Tumor; Breast Neoplasms; CA-19-9 Antigen; Carcinoembryonic Antigen; Case-Control Studies; Deoxyguanosine; Early Detection of Cancer; Female; Humans; Keratin-19; Middle Aged; Phosphopyruvate Hydratase

The objective of the present study was to characterize the role of novel resveratrol (Res) analogs: 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1, 2-diol} (HPIMBD) and 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) as potent antioxidants against breast cancer. Non-neoplastic breast epithelial cell lines MCF-10A and MCF-10F were treated with 17β-estradiol (E2), Res, HPIMBD, and TIMBD for up to 72 h. mRNA and protein levels of antioxidant genes, superoxide dismutase 3 (SOD3) and N-quinoneoxidoreductase-1 (NQO1) and transcription factors, nuclear factor erythroid 2-related factor (Nrf) 1, 2 and 3 were quantified after the above treatments. Generation of reactive oxygen species (ROS) was measured by CM-H2-DCFDA and oxidative-DNA damage was determined by measuring 8-hydroxy-2-deoxyguanosine (8-OHdG). HPIMBD and TIMBD scavenged cellular ROS production, attenuated oxidative DNA damage, increased mRNA and protein expression levels of SOD3 and NQO1 and activated Nrf signaling pathway. Our studies demonstrate that HPIMBD and TIMBD have the potential as novel antioxidants to prevent development of breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Anticarcinogenic Agents; Antioxidants; Breast; Breast Neoplasms; Catechols; Cell Line; Cell Proliferation; Cell Survival; Deoxyguanosine; Dietary Supplements; DNA Damage; Enzyme Induction; Estradiol; Female; Humans; NAD(P)H Dehydrogenase (Quinone); Oxidative Stress; Reactive Oxygen Species; Resveratrol; Schiff Bases; Signal Transduction; Stilbenes; Superoxide Dismutase

Normal tissue reactions are therapy limiting factor for the effectiveness of the radiotherapy in cancer patients. DNA repair and apoptosis are estimated to be critical players of adverse effects in response to radiotherapy. Our aim was to define the association of DNA repair (ERCC1 and XPC) and apoptotic (BCL2, CASP3 and NFKB1) gene expression, DNA damage levels, apoptosis changes and DNA repair gene variations with the risk of acute side effects in breast cancer patients. The study included 100 women with newly diagnosed breast cancer; an experimental case group (n=50) with acute side effects and the control group (n=50) without side effects. Gene expression was analyzed by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). Micronucleus (MN) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) assays were performed to compare the DNA damage levels. Apoptosis was examined by TDT-mediated dUTP-biotin nick end-labeling (TUNEL) staining. ERCC1 rs3212986 and XPC rs3731055 polymorphisms were genotyped by real-time PCR technique. No significantly correlation of DNA repair and apoptosis gene expression and DNA damage levels with acute side effects in response to radiotherapy. Also, there was no association between apoptosis levels and acute effects. ERCC1 rs3212986 CC genotype showed a protective effect against radiotherapy-induced acute reactions (p<0.001; OR: 0.21; 95% CI= 0.08-0.52). Our results suggest that apoptosis and DNA damage levels are not associated with acute radiosensitivity. DNA repair may affect the risk of acute reactions. Further studies are needed to validate the current findings.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Apoptosis; Breast Neoplasms; Carcinoma, Ductal; Carcinoma, Lobular; Caspase 3; Deoxyguanosine; DNA Fragmentation; DNA Repair; DNA-Binding Proteins; Endonucleases; Female; Gamma Rays; Gene Expression Regulation, Neoplastic; Humans; In Situ Nick-End Labeling; Micronucleus Tests; Middle Aged; NF-kappa B p50 Subunit; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-bcl-2; Radiation Tolerance; Signal Transduction; Skin

Alcohol consumption is associated with increased breast cancer risk; however, the underlying mechanisms that contribute to mammary tumor initiation and progression are unclear. Alcohol is known to induce oxidative stress and DNA damage; likewise, p53 is a critical modulator of the DNA repair pathway and ensures genomic integrity. p53 mutations are frequently detected in breast and other tumors. The impact of alcohol on p53 is recognized, yet the role of p53 in alcohol-induced mammary carcinogenesis remains poorly defined. In our study, we measured alcohol-mediated oxidative DNA damage in MCF-7 cells using 8-OHdG and p-H2AX foci formation assays. p53 activity and target gene expression after alcohol exposure were determined using p53 luciferase reporter assay, qPCR, and Western blotting. A mechanistic study delineating the role of p53 in DNA damage response and cell cycle arrest was based on isogenic MCF-7 cells stably transfected with control (MCF-7/Con) or p53-targeting siRNA (MCF-7/sip53), and MCF-7 cells that were pretreated with Nutlin-3 (Mdm2 inhibitor) to stabilize p53. Alcohol treatment resulted in significant DNA damage in MCF-7 cells, as indicated by increased levels of 8-OHdG and p-H2AX foci number. A p53-dependent signaling cascade was stimulated by alcohol-induced DNA damage. Moderate to high concentrations of alcohol (0.1-0.8% v/v) induced p53 activation, as indicated by increased p53 phosphorylation, reporter gene activity, and p21/Bax gene expression, which led to G0/G1 cell cycle arrest. Importantly, compared to MCF-7/Con cells, alcohol-induced DNA damage was significantly enhanced, while alcohol-induced p21/Bax expression and cell cycle arrest were attenuated in MCF-7/sip53 cells. In contrast, inhibition of p53 degradation via Nutlin-3 reinforced G0/G1 cell cycle arrest in MCF-7 control cells. Our study suggests that functional p53 plays a critical role in cellular responses to alcohol-induced DNA damage, which protects the cells from DNA damage associated with breast cancer risk.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alcohol Drinking; bcl-2-Associated X Protein; Breast Neoplasms; Cell Line, Tumor; Cell Transformation, Neoplastic; Cyclin-Dependent Kinase Inhibitor p21; Deoxyguanosine; DNA Damage; DNA Repair; Ethanol; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Histones; Humans; Imidazoles; MCF-7 Cells; Oxidative Stress; Piperazines; Proto-Oncogene Proteins c-mdm2; RNA Interference; RNA, Small Interfering; Tumor Suppressor Protein p53

Chemotherapy is less often prescribed in older individuals due to concerns about post-treatment morbidity and quality of life. We evaluated the physical performance of breast cancer survivors treated with and without adjuvant chemotherapy.. We conducted a case-control study in 56 estrogen receptor positive breast cancer survivors (BCS) on adjuvant aromatase inhibitors 1-2years after definitive surgery. Cases had received adjuvant chemotherapy (n=27; age 70.5±3.6years) versus age-matched controls who had not (n=29; age 70.0±4.3years). Measures of grip strength, physical activity and performance, walking speed, fatigue, and self-reported physical function were collected. Biological correlates of inflammation, frailty and markers of DNA and RNA oxidation were compared.. Grip strength (controls: 21±7.4 vs.. 29.7±5.0kg, p=0.20), physical activity (5403±3204 vs. 6801±9320steps/day, p=0.45), physical performance (short physical performance battery score: 10.1±1.8 vs. 10.4±1.1, p=0.52) and long-distance walking speed (1.2±0.21 vs. 1.3±0.41m/s, p=0.17) were similar between the two groups. Self-reported physical function was marginally lower in cases than controls (controls: 72±24 vs.. 57±34AU, p=0.07). Fatigue disruptiveness was not different between groups (controls: 11.1±13.0 vs.. 15.7±16.2AU, p=0.24). Similarly, the inflammation, oxidation, and frailty markers did not present a significant difference between groups, except for vitamin D levels (p=0.04).. Older women who received chemotherapy reported having slightly lower physical function, but a similar physical performance compared to women who did not. These data suggest that older BCS treated with chemotherapy recover to an extent similar to survivors who only received hormonal therapy.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Activities of Daily Living; Aged; Aromatase Inhibitors; Biomarkers; Breast Neoplasms; Cancer Survivors; Case-Control Studies; Chemotherapy, Adjuvant; Cross-Sectional Studies; Deoxyguanosine; Exercise; Fatigue; Female; Fibrin Fibrinogen Degradation Products; Guanine; Guanosine; Hand Strength; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Interleukin-6; Oxidation-Reduction; Pyrimidines; Serum Albumin; Tandem Mass Spectrometry; Tumor Necrosis Factor-alpha; Vitamin D; Walking Speed

A nontoxic chemopreventive intervention efficacious against different subtypes of breast cancer is still a clinically unmet need. The present study was undertaken to determine the efficacy of an Ayurvedic medicine phytochemical (Withaferin A, [WA]) for chemoprevention of breast cancer and to elucidate its mode of action.. Chemopreventive efficacy of WA (4 and 8 mg/kg body weight) was determined using a rat model of breast cancer induced by N-methyl-N-nitrosourea (MNU; n = 14 for control group, n = 15 for 4 mg/kg group, and n = 18 for 8 mg/kg group). The mechanisms underlying breast cancer chemoprevention by WA were elucidated by immunoblotting, biochemical assays, immunohistochemistry, and cytokine profiling using plasma and tumors from the MNU-rat (n = 8-12 for control group, n = 7-11 for 4 mg/kg group, and n = 8-12 for 8 mg/kg group) and/or mouse mammary tumor virus-neu (MMTV-neu) models (n = 4-11 for control group and n = 4-21 for 4 mg/kg group). Inhibitory effect of WA on exit from mitosis and leptin-induced oncogenic signaling was determined using MCF-7 and/or MDA-MB-231 cells. All statistical tests were two-sided.. Incidence, multiplicity, and burden of breast cancer in rats were decreased by WA administration. For example, the tumor weight in the 8 mg/kg group was lower by about 68% compared with controls (8 mg/kg vs control, mean = 2.76 vs 8.59, difference = -5.83, 95% confidence interval of difference = -9.89 to -1.76, P = .004). Mitotic arrest and apoptosis induction were some common determinants of breast cancer chemoprevention by WA in the MNU-rat and MMTV-neu models. Cytokine profiling showed suppression of plasma leptin levels by WA in rats. WA inhibited leptin-induced oncogenic signaling in cultured breast cancer cells.. WA is a promising chemopreventative phytochemical with the ability to inhibit at least two different subtypes of breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetyl Coenzyme A; Aldehyde Dehydrogenase 1 Family; Animals; Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Cell Cycle; Cytokines; Deoxyguanosine; Electron Transport Complex III; Female; Forkhead Transcription Factors; Humans; Ki-67 Antigen; Lactic Acid; Leptin; Malates; Mammary Neoplasms, Experimental; Mammary Tumor Virus, Mouse; MCF-7 Cells; Methylnitrosourea; Mice; Mitosis; Mitotic Index; Rats; Receptors, Estrogen; Retinal Dehydrogenase; Retroviridae Infections; Signal Transduction; Tumor Burden; Tumor Virus Infections; Withanolides

Blood levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured by enzyme immunoassay after overnight fasting in untreated breast cancer and endometrial cancer patients (N=170) of mainly postmenopausal age with and without type 2 diabetes mellitus. The concentrations of 8-OHdG in patients with breast cancer were higher than in patients with endometrial cancer and in patients with breast cancer and diabetes in comparison with patients with breast cancer without diabetes. No correlations of blood 8-OHdG levels with glycemia, age, and clinical stage of disease were detected. In cancer patients with diabetes, the concentration of 8-OHdG increases proportionally to the increase in body mass index, though this does not lead to disappearance of the above differences between patients with breast cancer and endometrial cancer by the level of 8-OHdG. The causes of the trend to a less favorable course of tumor process in patients with breast cancer and diabetes in comparison with endometrial cancer and diabetes deserve further studies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Body Mass Index; Breast Neoplasms; Deoxyguanosine; Diabetes Mellitus, Type 2; Endometrial Neoplasms; Female; Humans; Middle Aged

We investigated whether urinary markers of nucleic acid oxidation are associated with an increased risk of cancer in type 2 diabetes patients.. Urine samples from 1381 newly diagnosed diabetes patients were assayed for the oxidatively modified guanine nucleosides 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo). Cox proportional hazards regression was used to examine the relationship between the urinary markers and cancer incidence.. The crude analyses showed an association between overall cancer and urinary excretion of the RNA oxidation marker 8-oxoGuo (unadjusted hazard ratio for cancer per natural log increase in 8-oxoGuo 1.35 [95% CI, 1.01-1.81]), however, in the adjusted analyses, no significant associations between 8-oxodG or 8-oxoGuo and overall cancer were found. For site-specific cancers 8-oxodG was associated with breast cancer in the crude analyses (unadjusted hazard ratio for breast cancer per natural log increase in 8-oxodG was 2.37 [95% CI, 1.07-5.26]), although the association was attenuated in the adjusted analyses (sex- and age-adjusted hazard ratio 2.15 [95% CI, 0.92-5.02] and multivariate adjusted hazard ratio1.98 [95% CI, 0.95-4.10]).. Urinary excretion of the nucleic acid oxidation markers 8-oxodG and 8-oxoGuo at the time of diagnosis was not associated with cancer overall in type 2 diabetes patients. For site-specific cancers, risk elevations were seen for breast cancer (8-oxodG). These findings should be examined in future and larger studies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers, Tumor; Breast Neoplasms; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA; DNA Damage; Female; Guanosine; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; RNA

To analyze whether oxidative stress (OS) changes are present in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) versus controls.. Oxidative stress was analyzed in serum and unstimulated saliva of three groups: Group 1 consisted of 24 patients who had been treated with intravenous bisphosphonates (ivBPs) and developed BRONJ, group 2 consisted of 20 patients who had received ivBPs and did not develop BRONJ, and group 3 comprised 17 control subjects. Reduced glutathione (GSH), malondialdehyde (MDA), oxidized glutathione (GSSG), and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxo-dG) levels, as well as the GSSG/GSH ratio, were measured.. Mean serum and saliva levels of MDA, GSSG, and 8-oxo-dG and the GSSG/GSH ratio were significantly higher in patients with BRONJ than in controls. We found no significant difference in OS according to BRONJ stage, sex, or location in the jaws. Logistic regression analysis revealed that the GSSG/GSH ratio was a significant factor predicting the development of BRONJ (P = 0.01).. Oxidative stress was detected in patients with BRONJ, and the GSSG/GSH ratio was the most significant OS variable found; it was a significant factor predicting the development of BRONJ.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Intravenous; Adrenal Cortex Hormones; Aged; Antineoplastic Agents; Biomarkers; Bisphosphonate-Associated Osteonecrosis of the Jaw; Breast Neoplasms; Case-Control Studies; Dental Plaque Index; Deoxyguanosine; Diphosphonates; DMF Index; Female; Glutathione; Glutathione Disulfide; Humans; Male; Malondialdehyde; Middle Aged; Multiple Myeloma; Oral Hygiene Index; Oxidative Stress; Saliva; Sex Factors

The intracellular redox environment plays an important role in the maintenance of proper cellular homeostasis and functions. Disturbances in redox equilibrium of cells result in pro-inflammatory conditions, and these inflammatory conditions can induce carcinogenesis or increase the malignant potential of the tumor. Oxidative stress or tissue damage can trigger toll-like receptor (TLR) family of receptors that are involved in altering the innate immune system. The present study was aimed at evaluating the level of oxidative damage markers in breast diseases by measuring the 8-hydroxydeoxyguanosine (8-OHdG), protein carbonyl (PC), malondialdehyde (MDA), and total antioxidant status (TAS) alterations in relation to expression of TLR-9. A significant increase in the level of oxidative damage markers was observed in breast carcinoma patients in comparison to benign and normal controls, which was accompanied by a significant decrease in TAS and expression of TLR-9 concentrations. 8-OHdG, PC, and MDA were negatively correlated with expression of TLR-9 and TAS levels. Altered levels of biomarkers of oxidative stress and TLR-9 among the malignant, benign, and controls suggest a correlation of oxidative stress and TLR signaling in the progression of disease in breast carcinoma patients. Receiver operating characteristic analysis depicts that expression of TLR-9 is a good indicator for distinguishing cancer patients from benign and normal controls. High accuracy, specificity, and sensitivity of oxidative stress markers and expression of TLR-9 can be used as discriminatory marker/s for efficient diagnosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Deoxyguanosine; Female; Humans; Malondialdehyde; Middle Aged; Oxidative Stress; Protein Carbonylation; Toll-Like Receptor 9

The aim of the study was to compare the radiation-induced oxidative stress response in blood samples from breast cancer patients that developed severe acute skin reactions during the radiotherapy, with the response in blood samples from patients with no side effects. Peripheral blood was collected from 12 breast cancer patients showing no early skin reactions after radiotherapy (RTOG grade 0) and from 14 breast cancer patients who developed acute severe skin reactions (RTOG grade 3-4). Whole blood was irradiated with 0, 5 and 2000mGy γ-radiation and serum was isolated. The biomarker for oxidative stress, 8-oxo-dG, was analyzed in the serum by a modified ELISA. While a significant radiation-induced increase of serum 8-oxo-dG levels was observed in serum of the RTOG 0 patients, no increase was seen in serum of the RTOG 3-4 patients. The radiation induced increase in serum 8-oxo-dG levels after 5mGy did not differ significantly from the increase observed for 2000mGy in the RTOG 3-4 cohort, thus no dose response relation was observed. A receiver operating characteristic (ROC) value of 0.97 was obtained from the radiation-induced increase in 8-oxo-dG indicating that the assay could be used to identify patients with severe acute adverse reactions to radiotherapy. The results show that samples of whole blood from patients, classified as highly radiosensitive (RTOG 3-4) based on their skin reactions to radiotherapy, differ significantly in their oxidative stress response to ionizing radiation compared to samples of whole blood from patients with no skin reactions (RTOG 0). Extracellular 8-oxo-dG is primarily a biomarker of nucleotide damage and the results indicate that the patients with severe acute skin reactions differ in their cellular response to ionizing radiation at the level of induction of oxidative stress or at the level of repair or both.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Disease; Adult; Aged; Biomarkers; Blood Cells; Breast Neoplasms; Cohort Studies; Deoxyguanosine; Dose-Response Relationship, Radiation; Female; Gamma Rays; Humans; Middle Aged; Oxidative Stress; Radiation Tolerance; Skin Diseases

Oxidative stress may be important in carcinogenesis and a possible risk factor for breast cancer. The urinary excretion of oxidatively generated biomolecules, such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), represents biomarkers of oxidative stress, reflecting the rate of global damage to DNA in steady state.. In a nested case-control design, we examined associations between urinary excretion of 8-oxodG and risk of breast cancer in a population-based cohort of 24,697 postmenopausal women aged 50 to 64 years with 3 to 7 years follow-up. The accruing cases of breast cancer were matched to controls by age at diagnosis, baseline age, and hormone replacement therapy (HRT). Spot urine samples collected at entry was analyzed for 8-oxodG by high-performance liquid chromatography with electrochemical detection. Incidence rate ratio (IRR; 95% confidence intervals) based on 336 matched pairs with all information was estimated per unit increase in 8-oxodG divided by creatinine for all and estrogen receptor (ER) positive and negative breast cancers.. There was a borderline significant positive association between 8-oxodG and risk of all breast cancer (IRR: 1.08; 1.00-1.17 per unit increase in nmol/mmol creatinine). This association was significant with respect to the risk of ER-positive cancer (IRR: 1.11; 1.01-1.23) and among women not using HRT (IRR: 1.11; 0.97-1.26) or with low dietary iron intake (IRR: 1.10; 1.06-1.37 per unit increase) for all breast cancer.. We observed positive association between 8-oxodG excretion and risk of especially ER-positive breast cancer.. Our results suggest that oxidative stress with damage to DNA is important for the development of breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Cohort Studies; Denmark; Deoxyguanosine; Diet; DNA Damage; Female; Follow-Up Studies; Humans; Middle Aged; Oxidative Stress; Postmenopause; Prospective Studies; Receptors, Estrogen; Risk Factors

Ductal carcinoma in situ (DCIS) is a noninvasive breast cancer wherein malignant cells are confined within a ductal lobular unit. Although less than half the cases of DCIS will progress to invasive disease, most women are treated aggressively with surgery, radiation, and/or hormone therapy due to the inability to clinically evaluate the extent and location of the disease. Intraductal therapy, in which a drug is administered directly into the mammary duct through the nipple, is a promising approach for treating DCIS, but the feasibility of instilling drug into a diseased duct has not been established.. Four to 6 weeks before their scheduled surgery, 13 women diagnosed with DCIS were subjected to cannulation of the affected duct. After both the absence of perforation and presence of dye in the duct were confirmed by ductogram, pegylated liposomal doxorubicin was instilled. Histopathologic assessment was performed after surgery to assess the treatment effects.. Of the 13 women enrolled in the study, 6 had their DCIS duct successfully cannulated without perforation and instilled with the drug. The treatment was well tolerated, and no serious adverse events have been reported. Biomarker studies indicated a general decrease in Ki-67 levels but an increase in annexin-1 and 8-hydroxydeoxyguanosine in the lumen of DCIS-containing ducts, which suggests a local response to pegylated liposomal doxorubicin treatment.. Intraductal therapy offers a nonsurgical strategy to treat DCIS at the site of disease, potentially minimizing the adverse effects of systemic treatment while preventing development of invasive cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Annexin A1; Antibiotics, Antineoplastic; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Deoxyguanosine; Doxorubicin; Feasibility Studies; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Ki-67 Antigen; Magnetic Resonance Imaging; Neoplasm Staging; Polyethylene Glycols; Preoperative Care; Prognosis

Preliminary data are confirmed on the more rare prevalence of family history of diabetes mellitus (DM) in cancer patients, mainly females, with diabetes in comparison with diabetics without cancer pathology. Familial diabetes does not worsen additionally tumor characteristics against the same in patients with non-familial diabetes. More than that, familial diabetes in diabetics with breast cancer goes together with lesser size of tumor and demonstrates an inclination to the rarer distant metastases in breast and endometrial cancer patients. The signs of systemic DNA damage (evaluated, in particular, on the basis of 8-OH-dG serum levels) are pronounced in postmenopausal diabetic cancer patients with familial diabetes in lesser degree than in non-familial variant of DM. In toto, this allows to consider family history of DM in patients with type-2 diabetes as a particular factor of tumor growth containment, which mechanisms and causes, warrant further studies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers, Tumor; Breast Neoplasms; Deoxyguanosine; Diabetes Mellitus, Type 2; DNA Damage; Endometrial Neoplasms; Female; Humans; Incidence; Male; Middle Aged; Postmenopause

In view of recent studies highlighting the prognostic relevance of expression and CpG island methylator phenotype (CIMP) of Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) in invasive duct cell carcinoma (IDC), we hypothesized in this article that impaired one-carbon metabolism might influence CIMP phenotype of BNIP3. In order to substantiate the prognostic relevance of BNIP3, we explored its association with 8-oxo-2'deoxyguanosine (8-oxodG), a marker of oxidative stress with prognostic relevance. BNIP3 expression and CIMP phenotype were studied using semi-quantitative RT-PCR and combined bisulfite restriction analysis (COBRA), respectively, in 56 IDC tumors. Eight polymorphisms in one-carbon metabolism were studied using PCR-RFLP and PCR-AFLP approaches. 8-oxodG was measured using competitive ELISA kit. BNIP3 was found to be upregulated in IDC (cases vs. controls: 0.94 ± 0.05 vs. 0.18 ± 0.08, P < 0.0001). COBRA analysis confirmed hypomethylation of BNIP3 promoter CpG island in these cases. CIMP phenotype of BNIP3 showed positive association with tubule formation (P = 0.034) and methionine synthase reductase (MTRR) A66G (P = 0.002); inverse association with cytosolic serine hydroxyl methyltransferase (cSHMT) C1420T (P < 0.005) and 8-oxodG (<10% vs. >10% methylation: 7.24 ± 2.77 ng/ml vs. 4.42 ± 2.93 ng/ml, P < 0.0005); and no association with nuclear pleomorphism or mitotic index or ER, PR, and HER statuses. Synergistic effect of MTR A2756G and MTRR A66G variants on BNIP3 hypermethylator phenotype was clearly evident (P < 0.0007). MTRR A66G and cSHMT C1420T polymorphisms influence CIMP phenotype of BNIP3, thus epigenetically regulating BNIP3 in breast cancer. The linear association between BNIP3 and 8-oxodG substantiates the role of BNIP3 as redox sensor as well as prognostic marker in breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Amplified Fragment Length Polymorphism Analysis; Breast Neoplasms; Carcinoma, Ductal, Breast; Deoxyguanosine; DNA Methylation; Epigenesis, Genetic; Female; Ferredoxin-NADP Reductase; Gene Expression Regulation, Neoplastic; Glycine Hydroxymethyltransferase; Humans; Membrane Proteins; Oxidative Stress; Phenotype; Polymorphism, Genetic; Prognosis; Promoter Regions, Genetic; Proto-Oncogene Proteins; Sequence Analysis, DNA

The study was designed to evaluate the markers of oxidative damage and to establish their diagnostic utility in breast carcinoma patients. Levels of 8-hydroxy-2-deoxyguanosine (8-OH-dG), protein carbonyl (PC), and malondialdehyde (MDA) along with total antioxidant status (TAS) were measured in breast carcinoma patients and controls. Receiver operating characteristic (ROC) analysis was done to study the diagnostic potential of the oxidative damage markers. Significant increases in oxidative damage markers were observed in breast carcinoma patients compared with the normal controls, which were accompanied by significant decrease in TAS. The logistic regression analysis revealed higher levels of oxidative stress marker and reduced level of TAS were significantly associated with breast cancer. ROC curves analysis demonstrates that 8-OHdG and PC are better indicators for distinguishing cancer patients from controls, followed by MDA and TAS. Our results indicate increased oxidative damage is associated with malignancy in breast cancer patients. High accuracy of oxidative stress markers in indicating cancer presence can be used as discriminatory makers for efficient diagnosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Antioxidants; Biomarkers, Tumor; Breast Neoplasms; Carcinoma; Deoxyguanosine; Female; Humans; Malondialdehyde; Middle Aged; Oxidative Stress; Protein Carbonylation

The aim was to investigate indicators related to DNA damage and cancer pathogenesis in Type II diabetes cases with breast cancer. It was planned to evaluate the relationship between these markers with oral antidiabetic drugs.. Fourty patients and 10 healthy individuals were included in the study. HIF-1α and 8-OHdG are examined in blood samples taken from these individuals with an ELISA Kit. Statistical analysis of data was performed with 95% confidence using Windows package program SPSS 15.0.. HIF-1α parameters were found to be meaningfully higher in the patient group than the controls in both pretreatment and posttreatment periods (p<0.05). No significant differences in terms of 8-OHdG between patients and controls. However, posttreatment serum HIF-1α ve 8-OHdG levels was found lower than pretreatment levels in patients receiving metformin, but not with pioglitazone. Conversely, serum 8-OHdG levels decreased significantly in these patients. When patients were evaluated according to the treatment groups (pioglitazone vs. metformin) no significant differences in terms of serum HIF-1? and 8-OHdG levels between treatment groups.. HIF-1α levels decreased significantly in the patient group receiving metformin. However, there was no significant difference in terms of HIF-1α levels in the patients receiving pioglitazone.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Oral; Blood Glucose; Breast Neoplasms; Case-Control Studies; Deoxyguanosine; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Metformin; Pioglitazone; Prognosis; Thiazolidinediones

The aim of this study was to examine the prognostic significance of carbonic anhydrase IX (CA-IX), an endogenous marker for tumor hypoxia; endoglin (CD105), a proliferation-associated and hypoxia-inducible glycoprotein and 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative DNA lesion, in breast cancer patients. Immunohistochemical expressions of CA-IX, CD105 and 8-OHdG, analyzed on paraffin-embedded tumor tissues from forty female breast cancer patients, were used to assess their prognostic implication on overall survival (OS) and relapse-free survival (RFS). Patients with high CA-IX expression (above cut-off value) had a higher occurrence of relapse (P = = 0.002). High CA-IX expression was significantly associated with shorter RFS (P < 0.001, hazard ratio (HR) 0.21) and shorter OS (P < 0.001, HR 0.19). Lymph node negative patients with high CA-IX expression had worse RFS (P = 0.031, HR 0.14) and OS (P = 0.005, HR 0.05). Patients with grade I&II tumors and high CA-IX expression showed shorter RFS (P = 0.028, HR 0.28) and OS (P = 0.008, HR 0.20). Worse OS (P = 0.046, HR 0.28) was found in subgroup of patients with grade II tumors and high CA-IX expression. Among all three markers, only high CA-IX expression was strong independent prognostic indicator for shorter OS (HR 4.14, 95% CI 1.28-13.35, P = 0.018) and shorter RFS (HR 3.99, 95% CI 1.38-11.59, P = 0.011). Elevated expression of CA-IX was an independent prognostic factor for decreased RFS and OS and a significant marker for tumor aggressiveness. CD105 had week prognostic value; whereas, 8-OHdG, in this study, did not provide sufficient evidence as a prognostic indicator in breast cancer patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Antigens, CD; Antigens, Neoplasm; Biomarkers, Tumor; Breast Neoplasms; Carbonic Anhydrase IX; Carbonic Anhydrases; Deoxyguanosine; Endoglin; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Lymphatic Metastasis; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Prognosis; Receptors, Cell Surface; Survival Rate; Tissue Array Analysis

This study was conducted to evaluate blood concentrations of inflammatory cytokines and oxidative stress-related biomarkers as risk factors of breast cancer and to determine the relation between these markers and antioxidant nutrient intake.. Study subjects were 134 patients with breast cancer and 149 controls. Total antioxidant capacity and concentrations of 8-isoprostane, 8-hydroxy-2'-deoxyguanosine, interleukin (IL)-1β, IL-6, and IL-8 of blood samples were determined. A food-frequency questionnaire was used to assess nutrient intake.. Patients with breast cancer had significantly higher blood levels of oxidative stress markers compared with control subjects. Plasma concentrations of IL-1β and IL-6 were significantly higher in patients with breast cancer compared with those of control subjects. In the pooled analysis, total antioxidant capacity was significantly decreased with increasing quartiles of carbohydrate intake but was increased with increasing quartiles of total vitamin A intake and vitamin C intake. In addition, 8-hydroxy-2'-deoxyguanosine concentration was decreased with increasing quartiles of vitamin A and β-carotene. No significant association was found between nutrient intake and cytokine concentrations.. These results suggest that oxidative stress and inflammation may be associated with the risk of breast cancer. Total vitamin A intake was negatively related to oxidative stresses, possibly modifying the risk of breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Antioxidants; Ascorbic Acid; beta Carotene; Biomarkers; Breast Neoplasms; Case-Control Studies; Deoxyguanosine; Diet; Diet Surveys; Dietary Carbohydrates; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Middle Aged; Oxidative Stress; Risk Factors; Surveys and Questionnaires; Vitamin A; Vitamins

To clarify the role of oxidative stress during breast carcinogenesis by studying the expression of 8-hydroxydeoxyguanosine (8-OHdG) (a marker of oxidative DNA damage) and 4-hydroxy-2-nonenal (HNE) (a marker of lipid peroxidation) during the different phases of breast carcinogenesis.. The study material consisted of a total of 219 patients: 31 with usual ductal hyperplasia (UDH), 25 with atypical ductal hyperplasia (ADH), 30 with ductal carcinoma in situ (DCIS) and 133 with invasive carcinoma. The expression of 8-OHdG and HNE were evaluated immunohistochemically. Both 8-OHdG (77.4%) and HNE (45.8%) expression was already seen in UDH lesions. Interestingly, the trend of these two immunostainings during breast carcinogenesis was diverse. 8-OHdG expression diminished significantly in invasive breast carcinomas compared to non-invasive lesions (P < 0.005 when set against non-invasive cohorts). Also within the same lesions, 8-OHdG expression was the most intensive in benign cells. Conversely, HNE immunostaining was strongest in invasive breast carcinomas (UDH versus invasive cohort, P = 0.015).. 4-hydroxy-2-nonenal as a marker of lipid peroxidation increases during breast carcinogenesis, reflecting the role of oxidative stress in the pathogenesis of breast cancer. However, 8-OHdG shows diminished levels in carcinomas, possibly resulting from the induction of DNA repair in these invasive lesions.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Aldehydes; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Cell Transformation, Neoplastic; Deoxyguanosine; DNA Repair Enzymes; Female; Humans; Hyperplasia; Lipid Peroxidation; Middle Aged; Oxidative Stress; Retrospective Studies

Triple-negative breast cancer (TNBC) and basal-like breast cancer (BLBC) are breast cancer subtypes with an especially poor prognosis. 8-Hydroxydeoxyguanosine (8-OHdG) is a widely used marker of oxidative stress and the redox-state-regulating enzymes peroxiredoxins (PRDXs) are efficient at depressing excessive reactive oxygen species. NF-E2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) are redox-sensitive transcription factors that regulate PRDX expression. This is the first study to assess oxidative stress and or cell redox state-regulating enzymes in TNBC and BLBC.. We assessed immunohistochemical expression of 8-OHdG, Nrf2, Keap1, PRDX III and PRDX IV in 79 women with invasive ductal breast carcinomas. Of these tumors, 37 represented TNBC (grade II-III tumors with total lack of ER, PR and human epidermal growth factor receptor 2 [HER2] expression). Control cases (n = 42) were ER-positive, PR-positive and HER2-negative. Of the 37 TNBCs, 31 had BLBC phenotype (TNBC with expression of cytokeratin 5/6 or epidermal growth factor receptor 1).. Patients with TNBC had worse breast cancer-specific survival (BCSS) than the control group (p = 0.015). Expression of 8-OHdG was significantly lower in TNBC than in the non-TNBC group (p < 0.005). 8-OHdG immunostaining was associated with better BCSS (p = 0.01), small tumor size (p < 0.0001) and low grade (p < 0.0005). Keap1 overexpression was observed in the TNBC cohort (p = 0.001) and Keap1-positive patients had worse BCSS than Keap1-negative women (p = 0.014). PRDX IV was overexpressed in the TNBC vs. the non-TNBC group (p = 0.022).. Cellular redox state markers may be promising targets when elucidating the pathogenesis of TNBC.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Breast Neoplasms; Carcinoma, Basal Cell; Carcinoma, Ductal, Breast; Cohort Studies; Deoxyguanosine; Female; Follow-Up Studies; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidative Stress; Peroxiredoxin III; Peroxiredoxins; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone

Epidemiological and experimental evidences strongly support the role of estrogens in breast tumor development. Both estrogen receptor (ER)-dependent and ER-independent mechanisms are implicated in estrogen-induced breast carcinogenesis. Tamoxifen, a selective estrogen receptor modulator is widely used as chemoprotectant in human breast cancer. It binds to ERs and interferes with normal binding of estrogen to ERs. In the present study, we examined the effect of long-term tamoxifen treatment in the prevention of estrogen-induced breast cancer. Female ACI rats were treated with 17β-estradiol (E2), tamoxifen or with a combination of E2 and tamoxifen for eight months. Tissue levels of oxidative stress markers 8-iso-Prostane F(2α) (8-isoPGF(2α)), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and oxidative DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG) were quantified in the mammary tissues of all the treatment groups and compared with age-matched controls. Levels of tamoxifen metabolizing enzymes cytochrome P450s as well as estrogen responsive genes were also quantified. At necropsy, breast tumors were detected in 44% of rats co-treated with tamoxifen+E2. No tumors were detected in the sham or tamoxifen only treatment groups whereas in the E2 only treatment group, the tumor incidence was 82%. Co-treatment with tamoxifen decreased GPx and catalase levels; did not completely inhibit E2-mediated oxidative DNA damage and estrogen-responsive genes monoamine oxygenase B1 (MaoB1) and cell death inducing DFF45 like effector C (Cidec) but differentially affected the levels of tamoxifen metabolizing enzymes. In summary, our studies suggest that although tamoxifen treatment inhibits estrogen-induced breast tumor development and increases the latency of tumor development, it does not completely abrogate breast tumor development in a rat model of estrogen-induced breast cancer. The inability of tamoxifen to completely inhibit E2-induced breast carcinogenesis may be because of increased estrogen-mediated oxidant burden.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Catalase; Deoxyguanosine; Dinoprostone; Estradiol; Estrogens; Female; Glutathione Peroxidase; Isoprostanes; Mammary Neoplasms, Experimental; Oxidative Stress; Rats; Superoxide Dismutase; Tamoxifen

8-Hydroxydeoxyguanosine (8-oxodG) is the commonly used marker of oxidative stress-derived DNA damage. 8-OxodG formation is regulated by local antioxidant capacity and DNA repair enzyme activity. Earlier studies have reported contradictory data on the function of 8-oxodG as a prognostic factor in different cancer types.. We assessed pre-operative serum 8-oxodG levels with an enzyme-linked immunosorbent assay in a well-defined series of 173 breast cancer patients. 8-OxodG expression in the nuclei of cancer cells from 150 of these patients was examined by immunohistochemistry.. The serum 8-oxodG levels and immunohistochemical 8-oxodG expression were in concordance with each other (P<0.05). Negative 8-oxodG immunostaining was an independent prognostic factor for poor breast cancer-specific survival according to the multivariate analysis (P<0.01). This observation was even more remarkable when ductal carcinomas only (n=140) were considered (P<0.001). A low serum 8-oxodG level was associated statistically significantly with lymphatic vessel invasion and a positive lymph node status.. Low serum 8-oxodG levels and a low immunohistochemical 8-oxodG expression were associated with an aggressive breast cancer phenotype. In addition, negative 8-oxodG immunostaining was a powerful prognostic factor for breast cancer-specific death in breast carcinoma patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Deoxyguanosine; Female; Humans; Immunohistochemistry; Middle Aged; Neoplasm Staging; Prognosis; Survival Analysis

Previous studies have suggested the importance of redox regulation in carcinogenesis. The aim of this study was to evaluate the prognostic role of altered redox homeostasis and oxidative DNA damage in patients with breast carcinoma before and during two cycles of chemotherapy.. This study included 30 patients whose serum samples were obtained on admission before treatment, and after the first and second cycles of chemotherapy, and 20 controls. We investigated serum total antioxidant status (TAS), thiobarbituric acid reacting substances (TBARS), total nitrite/nitrate (NOx), nitrotyrosine (NT), and 8-hydroxydeoxy-guanosine (8-OHdG), as well as antioxidant enzyme activities, such as glutathione peroxidase (GPx), glutathione reductase (GRx).. TBARS, NOx, NT and 8-OHdG concentrations were significantly increased, while antioxidant enzyme activities and TAS were significantly decreased in patients when compared to controls. A concurrent increase in TBARS, NOx, NT, and 8-OHdG and a decrease in antioxidant enzyme activities and TAS were also seen after chemotherapy. No difference was observed in the second cycle of chemotherapy when compared with the first course.. In conclusion, decreased activities of these antioxidant enzymes and low TAS concentrations observed in our study might be due to the depletion of the antioxidant defense system to combat the free radical storm produced by chemotherapy. We suggest that the increased 8-OHdG and other oxidative/nitrosative stress products that we have measured in breast cancer patients may be prognostic risk factors for the magnitude of oxidation in serum.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Biomarkers, Tumor; Breast Neoplasms; Deoxyguanosine; DNA Damage; Female; Humans; Middle Aged; Nitrates; Nitrites; Nitrosation; Oxidation-Reduction; Oxidative Stress; Prognosis; Thiobarbituric Acid Reactive Substances; Tyrosine

Telomeres play a critical role in maintaining the integrity and stability of the genome, and are susceptible to oxidative damage after telomere shortening to a critical length. In the present study, we explored the role of white blood cell DNA telomere length on breast cancer risk, and examined whether urinary 15-F(2)-isoprostanes (15-F(2t)-IsoP) and 8-oxo-7,8-dihydrodeoxyguanosine (8-oxodG) or dietary antioxidant intake modified the relationship between telomere length and breast cancer risk. A population-based case-control study-the Long Island Breast Cancer Study Project-was conducted among 1,067 cases and 1,110 controls. Telomere length was assessed by quantitative PCR. Overall, the mean levels of telomere length (T/S ratio), 15-F(2t)-IsoP and 8-oxodG were not significantly different between cases and controls. Among premenopausal women only, carrying shorter telomeres (Q3 and Q4), as compared with the longest (Q1), was associated with significantly increased breast cancer risk. Age-adjusted OR and 95% CI were 1.71 (1.10-2.67) and 1.61 (1.05-2.45). The 5-F(2t)-IsoP and 8-oxodG biomarkers did not modify the telomere-breast cancer association. A moderate increase in breast cancer risk was observed among women with the shortest telomeres (Q4) and lower dietary and supplemental intake of beta-carotene, vitamin C or E intake [OR (95% CI) = 1.48 (1.08-2.03), 1.39 (1.01-1.92) and 1.57 (1.14-2.18), respectively], although the trend test exhibited statistical significance only within the lower vitamin E intake subgroup (p(trend) = 0.01). These results provided the strongest evidence to date that breast cancer risk may be affected by telomere length among premenopausal women or women with low dietary intake of antioxidants or antioxidant supplements.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antioxidants; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Deoxyguanosine; Female; Humans; Isoprostanes; Oxidative Stress; Polymerase Chain Reaction; Premenopause; Risk Factors; Telomere

Evaluation of altered urinary nucleosides before and after tumor removal of breast cancer (BCa).. Targeted metabolite profiling of 14 urinary nucleosides was conducted with both pre- and post-operative female patients with BCa (n=150, age: 46.6+/-7.7 years), and female controls (n=150, age: 46.8+/-7.7 years) by liquid chromatography-tandem mass spectrometry coupled to on-line extraction.. Levels of modified nucleosides (5-hydroxymethyl-2'-deoxyuridine, P<0.001; 8-hydroxy-2'-deoxyguanosine, P<0.001; 1-methyladenosine, P<0.02; N(2),N(2)-dimethylguanosine, P<0.001) were significantly higher in pre-operative patients than in both normal controls and post-operative patients.. This approach could be used to further understand the pathogenesis of BCa as well as to evaluate the effects of medical treatment.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenosine; Adult; Breast Neoplasms; Chromatography, Liquid; Deoxyguanosine; Female; Guanosine; Humans; Mastectomy; Middle Aged; Nucleosides; Oxidative Stress; Postoperative Period; Reactive Oxygen Species; Tandem Mass Spectrometry; Thymidine

Hypoxia is a predictor of poor patient survival in several cancers, including breast carcinomas. One possible mechanism is genomic instability induced by oxic stress. In this study we examined this possible mechanism by exposing an in vivo breast cancer model to hypoxia/reoxygenation. MMTV-Neu transgenic mice were exposed to cycling acute (AH) or chronic hypoxia (CH) before (early) or after (late) tumour detection to study effects of hypoxia on tumour initiation and progression, respectively. We observed no effect of the hypoxic exposures on times to first tumour detection, but we saw a trend of early AH-exposed mice to develop more tumours and macrometastases than CH-exposed mice. Unexpectedly, but consistent with these findings, we observed significantly reduced 8-oxo-dG lesions levels in the mammary tissue with the greatest difference observed between the air control (AC) and AH-exposed groups. In the late gassing group, there was a similar trend for reduced 8-oxo-dG lesion levels, but interestingly mice that developed macroscopic lung metastases demonstrated significantly increased levels of 8-oxo-dG lesions in their tumours relative to those that did not, irrespective of the gassing exposure. A trend for increased macrophage content was observed in tumours from mice exposed to acute hypoxia. Our results indicate that oxic stress induced by hypoxia/reoxygenation is unlikely to be a major factor driving tumour progression of established MMTV-Neu tumours but suggest that acute and chronic hypoxia may affect tumour incidence and metastasis when applied prior to tumour development.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Disease; Animals; Breast Neoplasms; Cell Hypoxia; Chronic Disease; Deoxyguanosine; Disease Progression; DNA Primers; DNA, Neoplasm; Female; Humans; Hypoxia; Mice; Mice, Transgenic; Neoplasm Metastasis; Receptor, ErbB-2

: Oxidant/antioxidant balance has been suggested as an important factor for initiation and progression of cancer. The objective of this study was to determine 8-hydroxydeoxyguanosine (8-OHdG) level as a marker of oxidative DNA damage, glutathione peroxidase (G-Px), and superoxide dismutase (SOD) activities as antioxidant activity, in sera from women with breast cancer.. : Forty-nine patients with malign breast tumor were included in the study. Blood samples were collected before the surgical operation. Serum level of 8-OHdG was measured with a competitive enzyme-linked immunusorbent assay kit, SOD, and G-Px activities were measured by spectrophotometric kits.. : 8-Hydroxydeoxyguanosine level and SOD activity were found to be increased in breast cancer group as compared with control group. Glutathione peroxidase activity in the breast cancer group was lower than those in the control group. The ratio of 8-OHdG/G-Px in breast cancer patients was found to be higher than those in the controls. There were correlations between 8-OHdG and CA19-9 (r = 0.77; P < 0.01); age and G-Px (r = -0.84; P < 0.05) in the breast cancer group.. : Data show that serum levels of 8-OHdG and SOD activities are higher in patients with breast cancer. Glutathione peroxidase activity is lower in the breast cancer group. Increased ratio of 8-OHdG/G-Px in breast cancer patients is the evidence for impaired oxidant/ antioxidant balance in breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Breast Neoplasms; Carcinoma; Case-Control Studies; Deoxyguanosine; Female; Fibroadenoma; Glutathione Peroxidase; Humans; Middle Aged; Oxidative Stress; Papilloma; Superoxide Dismutase

Prolonged exposure to radiation from radionuclei used in medical research can cause DNA damage and mutation, which lead to several diseases including cancer. Radioactivity-based experiments are expensive and associated with specialized training, dedication of instruments, approvals, and cleanup with potential hazardous waste. The objective of this study was to find an alternative to the use of radioactivity in medical research using nucleic acid chemistry. FITC-labeled oligonucleotides that contain wild-type (wt) and modified base (8-oxo-G) at the same position and their complementary unlabeled strand were synthesized. Purified DNA repair enzyme, OGG1, and nuclear lysates from MCF-7 breast cancer cells were incubated with double-stranded FITC-labeled wt and 8-oxo-G oligonucleotide to demonstrate the OGG1 incision assay. We found that FITC-coupled oligonucleotides do not impose a steric hindrance during duplex formation, and the fluorescence intensity of the oligonucleotide is comparable with the intensity of the radioactive oligonucleotide. Moreover, we have seen that the OGG1 incision assay can be performed using these fluorescence oligonucleotides, replacing conventional use of radiolabeled oligonucleotides in the assay. Although the use of fluorescent-labeled oligonucleotides was described in detail for incision assays, the technique can be applied to replace a broad range of experiments, where radioactive oligonucleotides are used, eliminating the hazardous consequences of radiation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenocarcinoma; Breast Neoplasms; Cell Line, Tumor; Deoxyguanosine; DNA Glycosylases; DNA Repair; Female; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Genes, BRCA1; Humans; Isotope Labeling; Neoplasm Proteins; Nucleic Acid Hybridization; Oligodeoxyribonucleotides; Oligonucleotide Probes; Radioisotopes; Recombinant Fusion Proteins; Substrate Specificity; Transfection; Ubiquitin-Protein Ligases

Several functions have been attributed to the BRCA1 protein. A recent study suggests that BRCA1 is involved in the cellular antioxidant response by inducing the expression of genes involved in the antioxidant defense system and thus conferring resistance to oxidative stress. It is possible that individuals with a BRCA1 mutation might be susceptible to the effects of oxidative stress. The aim of this study was to evaluate whether women with a BRCA1 mutation exhibit increased indicators of oxidative stress.. We measured 3 markers of oxidative stress in vivo, the amounts of serum malondialdehyde and protein thiols, and 8-oxo-2'-deoxyguanosine (8-oxodG) levels in 25 unaffected BRCA1 mutation carriers and 25 noncarrier control subjects.. There was no significant difference in serum malondialdehyde levels (P=.41), serum thiol levels (P=.85), or the number of 8-oxodG lesions (P=.49) in BRCA1 mutation carriers versus noncarriers.. The results of this study suggest that the presence of a heterozygous BRCA1 mutation is not associated with increased levels of indicators of oxidative stress in serum or lymphocytes. Future studies are warranted to evaluate whether strategies aimed at minimizing oxidative stress might aid in the prevention of hereditary breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Breast Neoplasms; Deoxyguanosine; DNA; Female; Genes, BRCA1; Heterozygote; Humans; Lipid Peroxidation; Malondialdehyde; Middle Aged; Mutation; Oxidation-Reduction; Oxidative Stress; Sulfhydryl Compounds; Young Adult

We previously reported that antiestrogen-liganded estrogen receptor beta (ERbeta) transcriptionally activates the major detoxifying enzyme quinone reductase (QR) (NAD(P)H:quinone oxidoreductase). Further studies on the functional role of ERbeta-mediated upregulation of antioxidative enzymes indicated protective effects against estrogen-induced oxidative DNA damage (ODD). We now report on in vivo and in vitro studies that show that ERbeta-mediated upregulation of QR are involved in the protection against estrogen-induced mammary tumorigenesis. Using the August Copenhagen Irish (ACI) model of estrogen-induced carcinogenesis, we observed that increased ODD and decreased QR expression occur early in the process of estrogen-induced mammary tumorigenesis. Prevention of ACI mammary gland tumorigenesis by tamoxifen was accompanied by decreased ODD and increased QR levels. These correlative findings were supported by our findings that downregulation of QR levels led to increased levels of estrogen quinone metabolites and enhanced transformation potential of 17beta-estradiol treated MCF10A non-tumorigenic breast epithelial cells. Concurrent expression of ERbeta and treatment with 4-hydroxytamoxifen decreased tumorigenic potential of these MCF10A cells. We conclude that upregulation of QR, through induction by tamoxifen, can inhibit estrogen-induced ODD and mammary cell tumorigenesis, representing a possible novel mechanism of tamoxifen prevention against breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Deoxyguanosine; DNA Damage; Estrogen Antagonists; Estrogen Receptor beta; Estrogens; Humans; Mammary Glands, Animal; NAD(P)H Dehydrogenase (Quinone); Oxidative Stress; Rats; Tamoxifen; Tumor Cells, Cultured

The objective of this study was to assess the dynamics of oxidative damage to cellular macromolecules such as proteins, lipids and DNA under conditions of oxidative stress triggering early stages of estrogen-dependent carcinogenesis. A rodent model of carcinogenesis was used. Syrian hamsters were sacrificed after 1, 3, 5 h and one month from the initial implantation of estradiol. Matching control groups were used. Kidneys as target organs for estradiol-mediated oxidative stress were excised and homogenized for biochemical assays. Subcellular fractions were isolated. Carbonyl groups (as a marker of protein oxidation) and lipid hydroxyperoxides were assessed. DNA was isolated and 8-oxodGuo was assessed. Electron paramagnetic resonance spectroscopy was used to confirm the results for lipid peroxidation. Exposition to estradiol in the rodent model leads to damage of macromolecules of the cell, including proteins and DNA, but not lipids. Proteins appear to be the primary target of the damage but are closely followed by DNA. It has previously been speculated that protein peroxides can increase DNA modifications. This time sequence was observed in our study. Nevertheless, the direct relation between protein and DNA damage still remains unsolved.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Breast Neoplasms; Cricetinae; Deoxyguanosine; DNA Damage; Electron Spin Resonance Spectroscopy; Estradiol; Female; Humans; Kidney; Lipid Peroxidation; Male; Mesocricetus; Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Oxidative Stress

Reactive oxygen species (ROS) causes damage to DNA, but the role of ROS in breast carcinoma is still not clear. The objective of this study was to measure the urinary 8-OHdG levels of breast cancer patients at each stage of carcinogenesis and assess its association with the development of breast cancer. Sixty patients with malignant breast tumors were matched with 60 control subjects of the same ages in this case control study. Urinary 8-OHdG levels were significantly higher among breast cancer patients than among the control subjects, after making adjustments for confounders such as smoking, coffee consumption and use of oral contraceptives. The breast cancer patients were divided into three groups based on the stages of their cancer; urinary 8-OHdG levels decreased with each stage of breast carcinoma. Using multiple regression and logistic models adjusted for other covariates, urinary 8-OHdG levels significantly correlated with the development of breast cancer. However, it was found that breast cancer was not significantly influenced by CYP1A1, CYP1M1 or NAT2 polymorphisms. In conclusion, it was found that oxygen radical generation occurred within carcinoma cells, but the role of polymorphism of specific genes in the development of breast cancer should be evaluated.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Arylamine N-Acetyltransferase; Breast Neoplasms; Case-Control Studies; Cytochrome P-450 CYP1A1; Deoxyguanosine; DNA Damage; Female; Glutathione Transferase; Humans; Middle Aged; Neoplasm Staging; Polymorphism, Genetic; Reactive Oxygen Species

Growing evidence suggests that oxidative damage to cells generates mutagenic 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG), which may initiate diseases related to aging and carcinogenesis. Kinetic measurement of 8-oxodG metabolism and repair in cells has been hampered by poor assay sensitivity and by difficulty characterizing the flux of oxidized nucleotides through the relevant metabolic pathways. We report here the development of a sensitive and quantitative approach to characterizing the kinetics and metabolic sources of 8-oxodG in MCF-7 human breast cancer cells by accelerator mass spectrometry. We observed that [(14)C]8-oxodG at medium concentrations of up to 2 pmol/ml was taken up by MCF-7 cells, phosphorylated to mono-, di-, and triphosphate derivatives, and incorporated into DNA. Oxidative stress caused by exposure of the cells to 17beta-estradiol resulted in a reduction in the rate of [(14)C]8-oxodG incorporation into DNA and an increase in the ratio of 8-oxodG monophosphate (8-oxodGMP) to 8-oxodG triphosphate (8-oxodGTP) in the nucleotide pool. 17beta-Estradiol-induced oxidative stress up-regulated the nucleotide pool cleansing enzyme MTH1 and possibly other Nudix-related pyrophosphohydrolases. These data support the conclusion that 8-oxodGTP is formed in the nucleotide pool by both 8-oxodG metabolism and endogenous reactive oxygen species. The metabolism of 8-oxodG to 8-oxodGTP, followed by incorporation into DNA is a mechanism by which the cellular presence of this oxidized nucleoside can lead to mutations.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA, Neoplasm; Female; Humans; Mass Spectrometry

Breast cancer course may be influenced by a profile of steroids and peptides produced by mammary fat. The study was concerned with assessment of hormonal (leptin and adiponectin production, adipocyte diameter and aromatase level) and progenotoxic factors which characterize DNA damage (8-OHdG) and such cancer promoters as tumor necrosis (TNF-alpha), interleukin-6 (IL-6), nitric oxide (NO), thiobarbiturate reactive products (TRP), macrophage/histiocyte infiltration, estrogen 4-hydroxylase expression (CYP1B1) in mammary fat located 1.5-2 cm or not less than 5 cm away from tumor edge. Thirty-three pairs of mammary fat samples from 23 menopausal and 10 cycling patients were used. Closer proximity of mammary fat involved intensified biosynthesis of estrogens (as shown by aromatase level) and their conversion to catechol derivatives (as shown by CYP1B1 concentration) as well as accumulation of 8-OH-dG. Smoking and hyperglycemic patients and those with considerable mammary fat volume revealed accumulations of anti-inflammatory and progenotoxic cytokines (IL-6 or TNF-alpha). Hence, hormonal/progenotoxic ratio in mammary fat can be identified both by topographic, systemic and environmental factors.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adipokines; Adiponectin; Adipose Tissue; Adult; Aged; Aromatase; Aryl Hydrocarbon Hydroxylases; Breast; Breast Neoplasms; Cytochrome P-450 CYP1B1; Deoxyguanosine; DNA Damage; Estrogens; Female; Humans; Interleukin-6; Leptin; Menopause; Middle Aged; Nitric Oxide; Premenopause; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

Recent studies from our laboratory provided evidence that part of the carcinogenic effects of ethanol consumption might be related to its in situ metabolism at cytosolic and microsomal levels, to the mutagen acetaldehyde and to hydroxyl and 1-hydroxyethyl radicals. In this work, we report on our experiments where Sprague-Dawley female rats were exposed to the standard Lieber & De Carli diet for 28 days. We observed: the induction of the (xanthineoxidoreductase mediated) cytosolic and microsomal (lipoxygenase mediated) pathways of ethanol metabolism; promotion of oxidative stress as shown by increased formation of lipid hydroperoxides; delay in the t-butylhydroperoxide induced chemiluminiscence, and a significant decrease in protein sulfhydryls. In addition, the epithelial cells showed ultrastructural alterations consisting of markedly irregular nuclei, with frequent invaginations at the level of the nuclear envelope, condensation of chromatin around the inner nuclear membrane, and marked dilatation of the nuclear pores showing filamentous material exiting to the cytoplasm. In conclusion, the presence in mammary epithelial cells of cytosolic and microsomal pathways of ethanol bioactivation to carcinogenic and to tumorigenic metabolites might play a role in alcohol promotion of breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetaldehyde; Alcohol Drinking; Animals; Breast Neoplasms; Central Nervous System Depressants; Cytosol; Deoxyguanosine; Diet; Ethanol; Female; Fluorescent Dyes; Free Radicals; Humans; Immunohistochemistry; Mammary Glands, Animal; Microscopy, Electron, Transmission; Microsomes; Oxidative Stress; Phenols; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds; Sulfoxides; Xanthine Oxidase; Xylenes

To evaluate the role of oxidative stress in breast cancer, we measured urinary levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP) and 8-oxodeoxyguanosine (8-oxodG) in 400 cases and 401 controls, participants of the Long Island Breast Cancer Study Project. We also analyzed the effect of different factors that are associated with oxidative stress and might influence 15-F(2t)-IsoP and 8-oxodG levels. We observed a statistically significant trend in breast cancer risk with increasing quartiles of 15-F(2t)-IsoP levels [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 0.81-1.94; OR, 1.53; 95% CI, 0.99-2.35; OR, 1.88; 95% CI, 1.23-2.88, for the 2nd, 3rd, and 4th quartile relative to the lowest quartile, respectively; P(trend) = 0.002]. Although it is possible that increased levels may reflect the stress associated with recent treatment, the positive association was also observed when the analyses were restricted to case women for whom chemotherapy and radiation therapy had not yet been initiated at the time of the urine collection. The association with the highest quartile compared with lowest quartile of 15-F(2t)-IsoP was similar across strata of age, physical activity, fruit and vegetable intake, alcohol intake, cigarette smoking, body mass index, and menopausal status. We did not observe any association of breast cancer risk with 8-oxodG levels, but when cases with radiation treatment were removed from the analysis, a significant inverse trend (P = 0.04) was observed. Among controls, levels of 15-F(2t)-IsoP were higher among current cigarette smokers but did not differ by the amount of physical activity, fruit and vegetable intake, alcohol intake, body mass index, and menopausal status. Among controls, levels of 8-oxodG were higher among postmenopausal women and current and former cigarette smokers but did not differ by the other factors. In summary, our results suggest that urinary markers of lipid peroxidation and oxidative DNA damage may be associated with breast cancer risk.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Analysis of Variance; Biomarkers; Breast Neoplasms; Carcinoma, Ductal, Breast; Deoxyguanosine; F2-Isoprostanes; Female; Humans; Middle Aged; New York; Oxidative Stress; Time Factors

About 30-40% of breast cancers lack steroid receptors (ER and/or PR) at diagnosis that worsen prognosis and limit the usage of hormone therapy. The aim of this paper has been to study the role of DNA-damaging factors as the potential modifiers of the receptor-negative tumors incidence.. The investigation consisted of two principal parts. In one of them ER and PR content was measured in breast cancer samples from 2284 primary patients (350 of them - current or previous smokers). In separately studied subgroup of 1010 patients 95 suffered with diabetes mellitus type II.. As it was shown, smokers and diabetics carry more frequently (p = or < 0.05) tumors with phenotypes ER+PR- and PR- only in the group of women with conserved menstrual cycle that is in case of relatively higher estrogenic stimulation. In another part of the investigation immunohistochemical study of DNA damage marker - 8-hydroxy-2-deoxyguanosine (8-OH-dG) in 16 R(-) and 18 R(+) breast cancer specimens demonstrated more frequent positive staining in the former group of samples (p = 0.05). Besides, as it was revealed in breast cancer cell line MCF-7 the combination of estradiol with aryl hydrocarbonic receptors agonist beta-naphtoflavone induced pronounced genotoxic damage (by 8-OH-dG content) in association with the loss of ER.. Thus, pro-genotoxic status (smoking, diabetes) and direct signs of genotoxic injury, in accordance with regularities of the phenomenon of switching of estrogen effects can be reckoned among the factors promoting the development of receptor-negative breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Deoxyguanosine; Diabetes Complications; DNA Damage; Female; Humans; Immunohistochemistry; Middle Aged; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Smoking

This study examined the expression of oxidative damage markers 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE) and nitrotyrosine using immunohistochemical techniques. In addition, DNA topoisomerase II binding protein 1 (TopBP1) and mismatch repair proteins 2 and 6 (MSH2 and MSH6) were immunostained in a series of 80 stage I invasive breast tumours, 26 in situ breast carcinomas and 12 benign breast hyperplasias. 8-OHdG, HNE and nitrotyrosine expression were considerably weaker in hyperplasias than in in situ lesions, which, in turn, showed less oxidative damage than T1N0 tumours. Hyperplasias and in situ tumours were all, at least moderately, positive for MSH2, and nearly all were positive for MSH6. Nitrotyrosine expression was associated with HNE (P<0.0005) and 8-OHdG (P=0.041) in the T1N0 cohort. To conclude, there is increasing oxidative stress during the early steps of breast carcinogenesis. On the other hand, a significant reduction in expression of mismatch repair proteins occurs during the progression of in situ lesions to invasive tumours.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Aldehydes; Base Pair Mismatch; Breast Neoplasms; Carrier Proteins; Deoxyguanosine; DNA-Binding Proteins; Female; Humans; Immunohistochemistry; Middle Aged; Nuclear Proteins; Oxidative Stress; Tyrosine

Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) is considered to be a biomarker of cellular oxidative stress and to be associated with carcinogenesis. To estimate the oxidative stress caused by radiotherapy, we used the enzyme-linked immunosorbent assay (ELISA) to monitor urinary 8-OHdG levels in 72 patients undergoing radiotherapy. Subjects consisted of 23 breast cancer patients undergoing post-operative external radiotherapy for breast conserving therapy, 12 tongue and seven prostate cancer patients undergoing interstitial radiotherapy, 19 esophageal cancer patients undergoing external radiotherapy and chemotherapy, and 11 cervical cancer patients undergoing external radiotherapy and brachytherapy with or without chemotherapy. Before radiotherapy, cervical cancer patients showed a higher urinary 8-OHdG level (16.0+/-8.8 ng/mg) than breast cancer patients (5.3+/-5.5 ng/mg, p=0.001). In the other three groups, urinary 8-OHdG levels were in the medium range (prostate cancer patients: 6.6+/-6.3 ng/mg; esophageal cancer patients: 8.8+/-11.1 ng/mg; tongue cancer patients: 10.2+/-6.7 ng/mg). Radiotherapy did not cause changes in the excretion level of urinary 8-OHdG in patients with breast, esophageal and tongue cancer. However, radiotherapy reduced 8-OHdG excretion levels in patients with cervical cancer, whereas interstitial radiotherapy transiently increased these levels in patients with prostate cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Biomarkers; Brachytherapy; Breast Neoplasms; Deoxyguanosine; DNA; Female; Humans; Middle Aged; Oxidative Stress; Radiotherapy; Radiotherapy Dosage; Regression Analysis

One-electron oxidation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) yielded a guanidinohydantoin derivative (dGh) and a spiroiminodihydantoin derivative (dSp), both putatively mutagenic products that may be formed in vivo. The nucleoside dGh was the major product at room temperature, regardless of pH. The results are contrary to previously published model studies using 2',3',5'-triacetoxy-8-oxo-7,8-dihydroguanosine (Luo, W.; Miller, J. G.; Rachlin, E. M.; Burrows, C. J. Org. Lett. 2000, 2, 613; Luo, W.; Miller, J.G.; Rachlin, E.M.; Burrows, C.J. Chem. Res. Toxicol. 2001, 14, 927), who observed a spiroiminodihydantoin derivative as the major product at neutral pH. Clearly, the functional groups attached to the ribose moiety of 8-oxodG influence the oxidation chemistry of the nucleobase derivative. To explore this chemistry in vivo, (14)C-labeled 8-oxodG was synthesized and incubated with growing MCF-7 human breast cancer cells, resulting in the incorporation of the compound into cellular DNA as measured by a novel accelerator mass spectrometry assay.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Binding, Competitive; Breast Neoplasms; Carbon Radioisotopes; Deoxyguanosine; DNA; Female; Guanidines; Guanosine; Humans; Hydantoins; Hydrogen-Ion Concentration; Oxidation-Reduction; Spiro Compounds; Time Factors; Tumor Cells, Cultured

Epirubicin fights cancer through topoisomerase II inhibition, hence producing DNA strand breaks that finally lead to cell apoptosis. But anthracyclines produce free radicals that may explain their adverse effects. Dexrazoxane--an iron chelator--was proven to decrease free radical production and anthracycline cardiotoxicity. In this article, we report the concentrations of cellular 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo) relative to 2'-deoxyguanosine (dGuo), and comet assay results from a study including 20 cancer patients treated with epirubicin. Plasma concentrations of vitamins A, E, C and carotenoids are also reported. All data were obtained before and immediately after epirubicin infusion. The ratios of 8-Oxo-dGuo to dGuo were measured in leukocyte DNA by HPLC-coulometry after NaI extraction of nucleic acids. Vitamins A and E and carotenoids were measured by HPLC-spectrophotometry. Vitamin C was measured by HPLC-spectrofluorimetry. Median 8-oxo-dGuo/dGuo ratios increased significantly from 0.34 to 0.48 lesions per 100,000 bases while per cent of tail DNA increased from 3.47 to 3.94 after chemotherapy 8-Oxo-dGuo/dGuo and per cent of tail DNA medians remained in the normal range. Only vitamin C decreased significantly from 55.4 to 50.3 microM Decreases in vitamins A, E, lutein and zeaxanthin were not significant, but concentrations were below the lower limit of the normal range both before and after chemotherapy. Only the correlation between comet assay results and vitamin C concentrations was significant (rho =-0.517, p = 0.023). This study shows that cellular DNA is damaged by epirubicin-generated free radicals which produce the mutagenic modified base 8-oxo-dGuo and are responsible for strand breaks. However, strand breaks are created not only by free radicals but also by topoisomerase II inhibition. In a previous study we did not find any significant change in urinary 8-oxo-dGuo excretion after adriamycin treatment. However, 8-oxo-dGuo may have increased at the end of urine collection as DNA repair and subsequent kidney elimination are relatively slow processes. In another study, authors used GC-MS to detect 8-oxo-dGuo in DNA and did not find any change after prolonged adriamycin infusion. Reasons for these apparent discrepancies are discussed.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Antibiotics, Antineoplastic; Ascorbic Acid; Breast Neoplasms; Comet Assay; Deoxyguanosine; DNA Damage; Epirubicin; Female; Free Radicals; Humans; Leukocytes; Middle Aged; Vitamin A; Vitamin E

The content of DNA damage marker 8-hydroxy-2-deoxyguanosine in 16 receptor-negative and 18 receptor-positive human breast neoplasms was measured by immunohistochemical methods. Positive staining was revealed in 81.3 and 50.0% samples of groups 1 and 2, respectively. The effect of arylhydrocarbon receptor agonist beta-naphthoflavone on the content of 8-hydroxy-2-deoxyguanosine and number of estrogen and progesterone receptors was evaluated in MCF-7 breast cancer cells. The degree of genotoxic damage significantly increased 1 h after combined treatment with estradiol and beta-naphthoflavone (in contrast to individual treatment) and remained practically unchanged in the follow-up period. According to the estrogen effect-switching phenomenon, genotoxic damage can contribute to the development of R(-)-breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; beta-Naphthoflavone; Breast Neoplasms; Deoxyguanosine; DNA Damage; Estradiol; Female; Humans; Immunohistochemistry; Middle Aged; Mutagenicity Tests; Receptors, Steroid

The effect of ethanol and acetaldehyde treatment on the removal of benzo[a]pyrene diol-epoxide (BPDE)-DNA adducts in the immortalized, human mammary epithelial cell line MCF-10F was examined. Treatment of cells with 15 mM and 25 mM ethanol resulted in significantly more BPDE-DNA adducts/unit DNA remaining at multiple time points, compared to controls. The half-life of BPDE-DNA adducts in cells exposed to both 15 and 25 mM ethanol were 11.9 and 12.3 h, respectively, compared to a half-life of 9.8 h for the control cells. In contrast, for cells exposed to acetaldehyde at doses of 2.5 and 5.0 microM no significant trend in BPDE-DNA adduct persistence occurred, compared to controls. The inhibition of adduct removal for cells treated with ethanol was not associated with any changes in cell viability due to ethanol exposure. However, BP-treated cells exposed to 25 mM ethanol exhibited a significant 2-fold increase in 8-oxo-deoxyguanosine (8-oxo-deG) adducts compared to BP-treated cells alone. No significant increase in 8-oxo-deG was observed for cells treated with BP and exposed to 5.0 microM acetaldehyde. Thus, ethanol exposure of human mammary epithelial cells is associated with a decreased capacity to remove BPDE-DNA adducts. This inhibitory effect of ethanol on adduct removal in part may be related to ethanol-associated oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetaldehyde; Benzo(a)pyrene; Breast Neoplasms; Cell Line, Tumor; Deoxyguanosine; DNA Adducts; DNA Damage; Epithelial Cells; Ethanol; Humans; Mammary Glands, Human; Oxidative Stress; Oxygen; Time Factors

The soy isoflavones, genistein (5,7,4'-trihydroxyisoflavone) and daidzein (7,4'-dihydroxyisoflavone), are representative phytoestrogens that function as chemopreventive agents against cancers, cardiovascular disease, and osteoporosis. However, recent studies indicated that genistein and/or daidzein induced cancers of reproductive organs in rodents, such as the uterus and vulva. To clarify the molecular mechanisms underlying the induction of carcinogenesis by soy isoflavones, we examined the ability of genistein, daidzein, and their metabolites, 5,7,3',4'-tetrahydroxyisoflavone (orobol), 7,3',4'-trihydroxyisoflavone (7,3',4'-OH-IF), and 6,7,4'-trihydroxyisoflavone (6,7,4'-OH-IF), to cause DNA damage and cell proliferation. An E-screen assay revealed that genistein and daidzein enhanced proliferation of estrogen-sensitive breast cancer MCF-7 cells, while their metabolites had little or no effect. A surface plasmon resonance sensor showed that binding of isoflavone-liganded estrogen receptors (ER) to estrogen response elements (ERE) was largely consistent with cell proliferative activity of isoflavones. Orobol and 7,3',4'-OH-IF significantly increased 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation in human mammary epithelial MCF-10A cells, while genistein, daidzein, and 6,7,4'-OH-IF did not. Experiments using isolated DNA revealed a metal-dependent mechanism of oxidative DNA damage induced by orobol and 7,3',4'-OH-IF. DNA damage was enhanced by the addition of endogenous reductant NADH, formed via the redox cycle. These findings suggest that oxidative DNA damage by isoflavone metabolites plays a role in tumor initiation and that cell proliferation by isoflavones via ER-ERE binding induces tumor promotion and/or progression, resulting in cancer of estrogen-sensitive organs.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Breast Neoplasms; Carcinogens; Cell Division; Cell Line; Cell Line, Tumor; Copper; Deoxyguanosine; DNA; DNA Damage; DNA Fragmentation; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Genistein; Humans; Isoflavones; Ligands; NAD; Oxidative Stress; Phosphorus Isotopes; Protein Binding; Receptors, Estrogen; Response Elements

Recent studies have shown that the antiestrogens tamoxifen and raloxifene may protect against breast cancer, presumably because of a blockade of estrogen receptor (ER)-mediated transcription. Another possible explanation is that antiestrogen-liganded ER transcriptionally induces genes that are protective against cancer. We previously reported that antiestrogen-liganded ERbeta transcriptionally activates the major detoxifying enzyme quinone reductase (QR) [NAD(P)H:quinone oxidoreductase]. It has been established that metabolites of estrogen, termed catecholestrogens, can form DNA adducts and cause oxidative DNA damage. We hypothesize that QR inhibits estrogen-induced DNA damage by detoxification of reactive catecholestrogens. We report here that physiological concentrations of 17beta-estradiol cause oxidative DNA damage, as measured by levels of 8- hydroxydeoxyguanine, in ER-positive MCF7 breast cancer cells, MDA-MB-231 breast cancer cells (ERalpha negative/ERbeta positive) and nontumorigenic MCF10A breast epithelial cells (very low ER), which is dependent on estrogen metabolism. Estrogen-induced 8-hydroxydeoxyguanine was inversely correlated to QR and ERbeta levels and was followed by downstream induction of the DNA repair enzyme XPA. Trans-hydroxytamoxifen, raloxifene, and the pure antiestrogen ICI-182,780 protected against estradiol-mediated damage in breast cancer cells containing ERbeta. This is most likely due to the ability of these antiestrogens to activate expression of QR via ERbeta. We conclude that up-regulation of QR, either by overexpression or induction by tamoxifen, can protect breast cells against oxidative DNA damage caused by estrogen metabolites, representing a possible novel mechanism of tamoxifen prevention against breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Breast Neoplasms; DNA Damage; DNA Repair; DNA-Binding Proteins; Enzyme Activation; Epithelial Cells; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptor Modulators; Estrogens; Female; Fulvestrant; Guanine; Humans; NAD(P)H Dehydrogenase (Quinone); Oxidative Stress; Raloxifene Hydrochloride; Receptors, Estrogen; Tamoxifen; Tumor Cells, Cultured; Xeroderma Pigmentosum Group A Protein

To develop predictive tests for individual radiosensitivity of tumor patients.. Acute skin reactions were clinically scored among 40 women after 46 Gy, given with 2 Gy fractions to breast and regional lymph nodes, adjuvant after surgery. The acute skin reactions were compared to the excretion of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) in urine, determined by high-performance liquid chromatography (HPLC) with electrochemical detector. Specimens of urine were collected before and during postoperative radiation treatment at given intervals. We compared a group of 9 patients with the most pronounced skin reactions with another group of 8 patients with almost no skin reactions at 46 Gy.. The level of 8-oxo-dG excreted in urine during 8 h was measured. After normalizing the excretion to irradiated volumes, dose per volume and excretion before irradiation, the 8-oxo-dG level in urine was significantly (p < 0.001) lower for the patients with pronounced skin reactions as compared to patients with minor skin reactions, at an accumulated dose of 12 Gy. In addition, the background level of 8-oxo-dG excreted before treatment started, was significantly (p = 0.043) lower for patients with minor skin reactions as compared to patients with pronounced skin reactions. The background level of 8-oxo-dG was corrected for body weight and normalized to BMI.. We suggest that the excretion of 8-oxo-dG into urine of breast cancer patients is a possible marker for acute radiosensitivity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Breast Neoplasms; Deoxyguanosine; Dose-Response Relationship, Radiation; Female; Humans; Predictive Value of Tests; Radiation Tolerance; Radiodermatitis; Radiotherapy, Adjuvant; Skin

A study was conducted to test the hypothesis that oxidative DNA damage caused by exposure to organochlorines is an important risk factor in breast cancer. This is the first study that evaluates this hypothesis by measuring 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, polychlorinated biphenyl (PCB) congeners, and isomers of bis (4-chlorophenyl)-1,1,1-trichloroethane (DDT) and bis (4-chlorophenyl)-2,2,2-dichloroethane (DDE) in cancerous and noncancerous tissue. We measured these compounds in 44 primary tumors (cancerous) and 21 benign breast biopsy (noncancerous) tissues. Overall, no significant differences were observed in the level of the organochlorines between the tissues. The median concentration for 8-OHdG was 10.5 fmol/mg DNA (1.7/10(5) deoxyguanosine residues), and 8.5 fmol/mg DNA (1.4/10(5) deoxyguanosine residues) in cancerous and noncancerous tissue, respectively. These values are similar to background levels. No significant differences were observed in 8-OHdG levels in cancerous versus noncancerous tissue, and no correlation was demonstrated between the organochlorines and 8-OHdG. The data thus do not support the hypothesis that oxidative DNA damage caused by exposure to organochlorines is an important risk factor in breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Breast Neoplasms; DDT; Deoxyguanosine; Dichlorodiphenyl Dichloroethylene; DNA Damage; Environmental Exposure; Environmental Pollutants; Female; Humans; Insecticides; Oxidative Stress; Polychlorinated Biphenyls; Risk Factors

To test the hypothesis that oxidative stress is involved in breast cancer, we compared the levels of 8-hydroxy-2-deoxyguanosine (8-oxo-dG), an oxidized DNA base common in cells undergoing oxidative stress, in normal breast tissues from women with or without breast cancer. We found that breast cancer patients (N = 76) had a significantly higher level of 8-oxo-dG than control subjects (N = 49). The mean ( +/- SD) values of 8-oxo-dG/10(5) dG, as measured by high-performance liquid chromatography electrochemical detection, were 10.7 +/- 15.5 and 6.3 +/- 6.8 for cases and controls, respectively (P = 0.035). This difference also was found by immunohistochemistry with double-fluorescence labeling and laser-scanning cytometry. The average ratios (x10(6)) of the signal intensity of antibody staining to that of DNA content were 3.9 +/- 7.2 and 1.1 +/- 1.4 for cases (N = 57) and controls (N = 34), respectively (P = 0.008). There was no correlation between the ages of the study subjects and the levels of 8-oxo-dG. Cases also had a significantly higher level of 8-hydroxy-2-deoxyguanosine DNA glycosylase/apurinic lyase (hOGG1) protein expression in normal breast tissues than controls (P = 0.008). There was no significant correlation between hOGG1 expression and 8-oxo-dG. Polymorphism of the hOGG1 gene was very rare in this study population. The previously reported exon 1 polymorphism and two novel mutations of the hOGG1 gene were found in three of 168 cases and two of 55 controls. In conclusion, normal breast tissues from cancer patients had a significantly higher level of oxidative DNA damage. The elevated level of 8-oxo-dG in cancer patients was not related to age or to deficiency of the hOGG1 repair gene.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Breast Neoplasms; Carbon-Oxygen Lyases; Deoxyguanosine; Deoxyribonuclease IV (Phage T4-Induced); DNA Damage; DNA-(Apurinic or Apyrimidinic Site) Lyase; DNA-Formamidopyrimidine Glycosylase; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; N-Glycosyl Hydrolases; Oxidative Stress; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational

Many of the major identified risk factors for breast cancer are associated with exposure to endogenous estrogen. In addition to the effects of estrogen as a growth factor, experimental and epidemiological evidence suggest that catechol metabolites of estrogen also contribute to estrogen carcinogenesis by both direct and indirect genotoxic mechanisms. O-Methylation catalyzed by catechol-O-methyltransferase (COMT) is a Phase II metabolic inactivation pathway for catechol estrogens. We and others have found that a polymorphism in the COMT gene, which codes for a low activity variant of the COMT enzyme, is associated with an increased risk of developing breast cancer; therefore, the goal of the current study was to investigate the role of decreased COMT activity on estrogen catechol levels and on oxidative DNA damage, as measured by 8-hydroxy-2'-deoxyguanosine (8-oxo-dG) levels. MCF-7 cells were pretreated with dioxin as a means to increase estrogen metabolism to catechol estrogens, then treated with estradiol (E2) +/- Ro 41-0960, a COMT-specific inhibitor. After extraction from culture medium, estrogen metabolites were separated using an high-performance liquid chromatography-electrochemical detection method. As expected, dioxin dramatically increased E2 oxidative metabolism, primarily to its 2-OH and 2-methoxy metabolites. The COMT inhibitor blocked 2-methoxy E2 formation. This was associated with increased 2-hydroxy E2 (2-OH E2) and 8-oxo-dG levels. In the presence of COMT inhibition, increased oxidative DNA damage was detected in MCF-7 cells exposed to as low as 0.1 microM E2, whereas in the absence of COMT inhibition, no increase in 8-oxo-dG was detected at E2 concentrations < or =10 microM. This study is the first to show that O-methylation of 2-OH E2 by COMT is protective against oxidative DNA damage caused by 2-OH E2, a major oxidative metabolite of E2.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Benzophenones; Breast Neoplasms; Catechol O-Methyltransferase Inhibitors; Deoxyguanosine; DNA Damage; DNA, Neoplasm; Enzyme Inhibitors; Estradiol; Estrogens, Catechol; Humans; Oxidative Stress; Tumor Cells, Cultured

Reactive oxygen species (ROS) induced damage to DNA plays a major role in carcinogenesis. In order to estimate the level of oxidative damage and its role in breast cancer, 8-hydroxy-2'-deoxyguanosine (8-OHdG) was determined in DNA isolated from human breast tissue. Furthermore, we investigated whether polymorphisms in genes for enzymes involved in generation and elimination of ROS had any association with the level of 8-OHdG in breast tissue. In this study, the level of 8-OHdG in DNA was measured by the high performance liquid chromatography-electrochemical detector (HPLC-ECD) method. Genotypes of cytochrome P450 (CYP)1A1, glutathione S-transferase (GST)M 1, GSTP1 and catechol O-methyltransferase (COMT) were determined by PCR-based restriction fragment length polymorphism analysis. A total of 61 Japanese patients were included in the study. The mean level of 8-OHdG in DNA of breast cancer tissues was 2.07 +/- 0.95 per 10(5) dG residues, while the mean level of 8-OHdG in DNA of non-cancerous breast tissues was 1.34 +/- 0.46 per 10(5) dG residues. The 8-OHdG levels in DNA of breast cancer tissues were significantly higher than those of their corresponding non-cancerous breast tissues (P < 0.0001). There was negative correlation between the clinical stage and the mean level of 8-OHdG in DNA of breast cancer tissues. Furthermore, patients with genotype of high GSTP1 activity had lower level of 8-OHdG in DNA of breast cancer tissues than others. On the contrary, the mean level of 8-OHdG in DNA of breast cancer tissues was higher among patients with genotype of high COMT activity. Our findings support the assumption that cancer cells are more exposed to oxidative stress than adjacent non-cancerous tissue. Genetic polymorphisms in enzymes involved in ROS metabolism may have a role in individual susceptibility to oxidant-related breast disease. At the same time, reduction of oxidative stress is thought to be a very important measure for primary prevention of breast cancer.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Breast Neoplasms; Catechol O-Methyltransferase; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP1A1; Deoxyguanosine; DNA Damage; Female; Genotype; Glutathione Transferase; Humans; Isoenzymes; Neoplasm Staging; Oxidation-Reduction; Reactive Oxygen Species; Receptors, Estrogen

Various markers of radiation-induced DNA damage including DNA oxidation were investigated in peripheral lymphocytes of 23 cancer patients prior to and one week after receiving radiotherapy with a cumulative dose of 54-70 Gy. Exposure to ionizing radiation nonsignificantly increased the ratio 2'deoxy-7-dihydro-8-oxoguanosine/2'deoxyguanosine (8-oxodG/dG) from 1.73 x 10(-5) to 3.33 x 10(-5). Frequencies of micronuclei significantly (p = 0.0003) increased from 6.4 to 38.9 per 1000 cells. The frequency of hypoxanthine-guanine-phosphoribosyltransferase (HPRT) mutant lymphocytes measured as 6-thioguanine resistant variant cells by 5-bromodeoxyuridine labeling, was elevated eight-fold, from 4.7 x 10(-6) to 36.2 x 10(-6) (p = 0.008) after termination of the radiotherapy, thus showing a clear response to the radiation treatment. No correlation between levels of oxidative DNA damage and frequencies of HPRT mutant lymphocytes or micronuclei could be established.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Antioxidants; Biomarkers; Breast Neoplasms; Bromodeoxyuridine; Deoxyguanosine; DNA Damage; Female; Head and Neck Neoplasms; Humans; Hypoxanthine Phosphoribosyltransferase; Male; Micronucleus Tests; Middle Aged; Neoplasms; Oxidation-Reduction; Prostatic Neoplasms; Smoking

The expression of the 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase (8-oxo-dGTPase) gene in human breast tumors was evaluated at the level of the single cell to better understand how breast tumor cells regulate expression in response to oxidative stress. Compared to normal breast ductal cells, the level of 8-oxo-dGTPase expression in the breast tumor cells increased from non-detectable levels in normal breast to expression in 30-85% of the tumor cells in individual tumors. There was no significant association between 8-oxo-dGTPase expression and tumor grade and metastatic malignancy. The upregulation of 8-oxo-dGTPase was not directly linked to the expression of cyclins D1 and D3, estrogen receptor, p53, Ki-67 and c-erbB-2, which are genes involved in cell cycle regulation and tumor growth. The elevated expression of 8-oxo-dGTPase in human breast ductal carcinoma cells appears to be a general characteristic of breast tumors and may provide the tumor cell with a cellular defense mechanism to prevent the incorporation of 8-hydroxy-deoxyguanosine during DNA replication.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Deoxyguanosine; DNA Repair Enzymes; Female; Gene Expression Regulation, Enzymologic; Humans; Ki-67 Antigen; Middle Aged; Phosphoric Monoester Hydrolases; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species

In order to estimate the level of oxidative damage and its role in breast cancer, the promutagenic oxidative lesion, 8-hydroxy-2'-deoxyguanosine (8-OHdG), was determined in DNA isolated from 75 human breast tissue specimens and from normal and transformed human breast cell lines, utilising a newly developed solid-phase immunoslot blot assay. The amount of 8-OHdG was found to be 0.25 +/- 0.03 pmol/microgram in normal breast tissue from reduction mammoplasty, 0.98 +/- 0.174 pmol/microgram in benign tumours and 2.44 +/- 0.49 pmol/microgram DNA in malignant breast tissue with invasive ductal carcinoma. The malignant tissue had a statistically significant 9.76-fold higher level of 8-OHdG than normal tissue (P < 0.001, Mann-Whitney). A statistically significant 12.9-fold (P = 0.004) higher endogenous formation of 8-OHdG was also observed in cultured breast cancer cells compared with normal breast epithelial cells. In addition, a significantly elevated level (3.35-fold higher, P < 0.05) of 8-OHdG observed in oestrogen receptor-positive compared with oestrogen-negative malignant tissues, and in breast cancer cell lines (9.3-fold higher, P = 0.007) suggests a positive relationship between 8-OHdG formation and oestrogen responsiveness. The extent of 8-OHdG adducts did not show a discernible correlation with either the age or the smoking status of the patients. These results indicate that the accumulation of 8-OHdG in DNA has a predictive significance for breast cancer risk assessment and is conceivably a major contributor in the development of breast neoplasia.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast; Breast Neoplasms; Deoxyguanosine; DNA Damage; DNA, Neoplasm; Female; Humans; Immunoblotting; Middle Aged; Oxidative Stress; Prognosis; Receptors, Estrogen; Smoking; Tumor Cells, Cultured

Topics: 8-Hydroxy-2'-Deoxyguanosine; Breast; Breast Neoplasms; Deoxyguanosine; DNA, Neoplasm; Female; Humans

8-Hydroxydeoxyguanosine (oh8dG) is a promutagenic DNA lesion produced by oxygen radicals, and a high level of 8-hydroxyguanine in breast cancers was previously demonstrated by the gas chromatography-mass-spectrometry method. To confirm the previous observation, the oh8dG levels of DNA of 22 breast cancers and corresponding adjacent non-cancerous breast tissues were analyzed by high performance liquid chromatography-electrochemical detector (HPLC-ECD) system, and the correlation of the oh8dG levels in breast cancer DNAs with clinical and immunohistochemical parameters was examined. However, the levels of oh8dG in DNA of breast cancers are not significantly different from those of corresponding non-cancerous breast tissues (P = 0.084) by the HPLC-ECD method. Furthermore, the oh8dG levels in breast cancers were not associated with p53 and erbB-2 immunoreactions, with expression of estrogen and progesterone receptors, and with clinical stage and histological grade. Thus, in contrast to the previous data, the present study using the HPLC-ECD method does not indicate an increase of oh8dG levels in breast cancers.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Breast; Breast Neoplasms; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA Adducts; DNA Damage; DNA, Neoplasm; Electrochemistry; Female; Free Radicals; Humans; Reactive Oxygen Species; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Tumor Suppressor Protein p53