Reducing mammary cancer risk through premature stem cell senescence

The reproductive capacity of the mammary epithelial stem cell is reduced coincident with the number of symmetric divisions it must perform. In a study of FVB/N mice with the transgene, WAP-TGFbeta1, we discovered that mammary epithelial stem cells were prematurely aged due to ectopic expression of TGF-beta1. To test whether premature aging of mammary epithelial stem cells would have an impact on susceptibility or resistance to mammary cancer, female littermates from FVB/N x WAP-TGF-beta1 mating were injected with mouse mammary tumor virus (MMTV) at 8-10 weeks of age. A total of 44 females were inoculated, maintained as breeders and observed for tumor development for up to 18 months. Only one mammary tumor appeared in 17 TGF-beta1 females while 15 were collected from 29 wild type sisters. Premalignant mammary epithelial cells in infected glands were identified by transplantation of single cell (1 x 10(5)) suspensions into nulliparous hosts and testing for hyperplastic outgrowth. Although the number of positive takes was significantly reduced with TGF-beta1 cells, both MMTV-infected TGF-beta1 and wild type cells produced hyperplastic outgrowths suggesting that premalignant transformation was achieved in each group. The results suggest a positive correlation between the procreative life-span of mammary epithelial stem cells and mammary cancer risk.     

Plasma cysteinylglycine levels and breast cancer risk in women

Cysteinylglycine, a prooxidant generated during the catabolism of glutathione, has been suggested to induce oxidative stress and lipid peroxidation, leading to the development of human cancers. Observational data relating cysteinylglycine status to breast cancer risk are lacking. We prospectively evaluated plasma cysteinylglycine levels and invasive breast cancer risk among 812 case-control pairs nested in the Women's Health Study, a completed randomized trial evaluating low-dose aspirin and vitamin E in middle-aged and older women. We additionally evaluated the effect modification by risk factors for oxidative stress, such as vitamin E assignment, alcohol consumption, obesity, and postmenopausal hormone use. Logistic regression controlling for matching factors, as well as other risk factors for breast cancer, was used to estimate relative risks (RR) and 95% confidence intervals (95% CI). All statistical tests were two sided. We observed no overall association between plasma cysteinylglycine and invasive breast cancer risk. However, higher cysteinylglycine levels were marginally associated with an increased risk of breast cancer in the high oxidative stress groups. Women in the highest quintile group of cysteinylglycine relative to the lowest group had multivariate RRs (95% CIs) of 1.64 (1.01-2.66; P(trend) = 0.04) in the vitamin E placebo group, 2.51 (1.01-6.24; P(trend) = 0.07) in the high alcohol intake group (>or=9 g/day), and 1.66 (0.97-2.84; P(trend) = 0.03) in the overweight and obese group. Our findings suggest that women who are susceptible to experiencing oxidative stress may be at a greater risk for developing breast cancer.     

Relationships between circulating hormone levels, mammographic percent density and breast cancer risk factors in postmenopausal women

Background Endogenous hormones and insulin-like growth factors (IGF) play a central role in breast cancer development. Mammographic density, an important breast cancer risk factor, has been associated with these biomarkers in premenopausal women. The aim of this study was to assess the relationships between circulating hormones, clinical features related to breast cancer risk and mammographic density in postmenopausal women. Subjects and methods The study included 226 postmenopausal women participating in a clinical prevention trial. We performed baseline measurements of mammographic percent density and circulating levels of estradiol, sex-hormone binding globulin (SHBG), follicle stimulating hormone (FSH), prolactin, C-terminal cross-link telopeptide, IGF-I, and IGF binding protein-3. Results Median age and time since last menses were 52 years and 15 months, respectively. Median body mass index was 24.1 kg/m². After adjusting for age and body mass index, estradiol was the only biomarker significantly correlated with mammographic density (r = 0.17; P = 0.04). Women with normal body mass index had higher mammographic density (P < 0.001), higher SHBG (P < 0.0001), higher FSH (P = 0.002) and lower estradiol levels (P = 0.01) than those who were overweight. Women who had previous biopsies for benign breast disease had a higher mammographic density (P = 0.006). Conclusions In these recently postmenopausal women, mammographic percent density is directly associated with circulating estradiol levels. Our results provide further support to the role of circulating hormones in breast cancer risk.     

Impact of breast cancer on anti-mullerian hormone levels in young women

Young women with breast cancer face treatments that impair ovarian function, but it is not known if malignancy itself impacts ovarian reserve. As more breast cancer patients consider future fertility, it is important to determine if ovarian reserve is impacted by cancer, prior to any therapeutic intervention. A cross-sectional study was conducted comparing if ovarian reserve, as measured by anti-mullerian hormone (AMH), follicle stimulating hormone (FSH), and inhibin B (inhB), differed between 108 women with newly diagnosed breast cancer and 99 healthy women without breast cancer. Breast cancer participants were ages 28–44 and were recruited from two clinical breast programs. Healthy women ages 30–44 without a history of infertility were recruited from gynecology clinics and the community. The median age (interquartile range) was 40.2(5.5) years for breast cancer participants and 33.0(4.6) years for healthy controls. The unadjusted geometric mean AMH levels (SD) for breast cancer participants and controls were 0.66(3.6) and 1.1(2.9) ng/mL, respectively. Adjusting for age, body mass index, gravidity, race, menstrual pattern, and smoking, mean AMH levels were not significantly different between breast cancer participants and healthy controls (0.85 vs. 0.76 ng/mL, p = 0.60). FSH and inhB levels did not differ by breast cancer status. In exploratory analysis, the association between AMH and breast cancer status differed by age (p-interaction = 0.02). AMH may be lower with breast cancer status in women older than 37. In younger women, AMH levels did not differ significantly by breast cancer status. Among the youngest of breast cancer patients, ovarian reserve as measured by AMH, FSH, and inhibin B did not differ significantly from healthy women of similar age. In older breast cancer patients, ovarian reserve may be adversely impacted by cancer status. These findings support the potential success and need for fertility preservation strategies prior to institution of cancer treatment.     

Sunlight,hormone replacement status and colorectal cancer risk in postmenopausal women

A reanalysis of the Women's Health Initiative (WHI) randomized clinical trial found a significant interaction between supplementation with vitamin D/calcium and estrogen therapy and the risk of colorectal cancer risk, with reduced risks from supplementation limited to the placebo arms of the estrogen trials. To explore whether the vitamin D effects are modified by estrogen therapy, we report a largely cross‐sectional, analysis of the association between sun exposure, which is an important vitamin D source, and colorectal cancer risk among postmenopausal women in the U.S. Radiologic Technologists study. Among 21,695 participants, there were a total of 108 cases. Sun exposure was based on time outdoors and on ambient ultraviolet radiation (UV) exposure based on residence linked to erythemal exposures derived from the Total Ozone Mapping Spectrometer database. Although there was no relationship between outdoor time or ambient UV measure and colorectal cancer risk in current hormone replacement therapy (HRT) users, in never/past HRT users, there was an inverse association with higher ambient UV exposure, RR for highest vs. lowest tertile = 0.40; 95% CI 017, 0.93; p for trend = 0.04. Non‐significant lower risks were also associated with higher levels of outdoor time (≥3.5 hr/week) in never/past HRT users. The interaction between both indicators of sun exposure and HRT and CRC risk was not significant. These data, although exploratory, are consistent with evidence from the WHI suggesting a decrease in colorectal cancer risk may be associated with vitamin D exposure among postmenopausal women who are not taking HRT, but not among current HRT users.     

Plasma leptin levels and risk of breast cancer in premenopausal women

Body mass index (BMI) is inversely related to the risk of premenopausal breast cancer, but the underlying biological mechanisms of this association are poorly understood. Leptin, a peptide hormone produced primarily by adipocytes, is a potential mediator of the BMI association because BMI and total body fat are positively associated with circulating leptin levels and leptin and its receptor are overexpressed in breast tumors. We conducted a prospective case-control study nested within the Nurses' Health Study II cohort examining the association between plasma leptin levels in premenopausal women and breast cancer risk. Leptin was measured in blood samples collected between 1996 and 1999. The analysis included 330 incident breast cancer cases diagnosed after blood collection and 636 matched controls. Logistic regression models, controlling for breast cancer risk factors, were used to calculate ORs and 95% CIs. After adjustment for BMI at age 18, weight change since age 18 to blood draw, and other breast cancer risk factors, plasma leptin levels were inversely associated with breast cancer risk (OR for top vs. bottom quartile = 0.55; 95% CI = 0.31-0.99; P(trend) = 0.04). Adjustment for BMI at blood draw attenuated the association (OR = 0.69; 95% CI = 0.38-1.23; P(trend) = 0.26). Our results suggest that leptin may be inversely associated with breast cancer risk, but it is unclear whether any part of this association is independent of BMI.     

Body size, hormone therapy and risk of breast cancer in Asian-American women

Historically, breast cancer rates have been low in Asia but rates have increased substantially in Asian-Americans for reasons that are not well understood. The authors conducted a population-based case-control study of breast cancer in Los Angeles County, which included 1,277 (450 Chinese, 352 Japanese, 475 Filipinos) women with incident, histologically confirmed breast cancer and 1,160 control subjects (486 Chinese, 311 Japanese, 363 Filipinos). A detailed in-person interview was conducted, which included questions on menopausal hormone therapy (HT) use, height, weight in each decade of life and reproductive factors. Breast cancer risk increased with increasing recent weight in postmenopausal women (p trend = 0.015). There was a significant 16% (95% CI = 2-35%) increase in risk per 10 kg of body weight in postmenopausal women. In both premenopausal and postmenopausal women, risk increased with increasing waist to hip ratio; this remained statistically significant after adjustment for recent weight in all subjects combined (p trend = 0.042). The increased risk associated with high recent weight in postmenopausal women was more apparent for women with high waist to hip ratio (p trend = 0.013). Use of HT was a significant risk factor; risk increased 26% per 5 years of current use of estrogen and progestin therapy (p trend = 0.017). The increased risk associated with high body weight was observed irrespective of HT use. Use of HT and high body size might have contributed to the rapid increase of breast cancer in Asian-Americans.     

Serum follicle-stimulating hormone and risk of epithelial ovarian cancer in postmenopausal women.

The "gonadotropin hypothesis" postulates that gonadotropin overstimulation of ovarian epithelium results in its increased proliferation and subsequent malignant transformation. To address this hypothesis, we assessed the association between prediagnostic serum levels of follicle-stimulating hormone (FSH) and the risk of epithelial ovarian cancer in postmenopausal women who were part of a case-control study nested within three prospective cohorts in New York City, Ume?, Sweden, and Milan, Italy. Case subjects were 88 women with primary invasive epithelial ovarian cancer diagnosed between 3 months and 13.1 years after the blood donation. Controls were 168 women who were free of cancer and matched the case on cohort, age, and enrollment date. Serum FSH was determined using a quantitative immunoradiometric assay. FSH concentrations were similar in women who subsequently received a diagnosis of epithelial ovarian cancer (median, 44.0 mIU/ml; range, 13.8-101.2) and in controls (median, 43.4 mIU/ml; range, 13.5-109.5; P = 0.17). Compared with women in the lowest third, women in the highest third of serum FSH were not at increased risk of epithelial ovarian cancer after an adjustment for potential confounders (odds ratio, 0.85; 95% confidence interval, 0.36-1.99). These observations provide no evidence for an association between circulating FSH and risk of epithelial ovarian cancer in postmenopausal women and do not appear to support the gonadotropin hypothesis of epithelial ovarian carcinogenesis.     

Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal women

BACKGROUND: In animal studies, prolactin has been found to be important for mammary epithelial development and its administration has been shown consistently to increase the rate of mammary tumor formation. Previous epidemiologic studies of prolactin and breast cancer risk in postmenopausal women have been limited in size, and the results have been inconsistent. We conducted a nested case-control study within the prospective Nurses' Health Study cohort to better determine the relationship between plasma prolactin levels and postmenopausal breast cancer risk. METHODS: Blood samples were collected from cohort members during the period from 1989 through 1990. Prolactin levels were measured by use of a microparticle enzyme immunoassay. Included in this analysis were 306 postmenopausal women who were diagnosed with breast cancer after blood donation but before June 1994. One or two postmenopausal control subjects were matched per case subject on the basis of age, postmenopausal hormone use, and time of day and month of blood collection; the study included a total of 448 control subjects. RESULTS: In conditional logistic regression analyses, a significant positive association was observed between plasma level of prolactin and postmenopausal breast cancer risk (highest versus lowest quartile, multivariate relative risk = 2.03; 95% confidence interval = 1.24-3.31; two-sided P for trend = .01). The relationship was independent of plasma sex steroid hormone levels and was similar after excluding case subjects diagnosed in the first 2 years after blood collection. CONCLUSIONS: These prospective data suggest that higher plasma prolactin levels are associated with an increased risk of breast cancer in postmenopausal women.     

Radiation therapy induced changes in male sex hormone levels in rectal cancer patients.

BACKGROUND AND PURPOSE: To determine the effect of curative radiation therapy (46-50 Gy) on the sex hormone levels in male rectal cancer patients. MATERIALS AND METHODS: Twenty-five male rectal cancer patients (mean age 65 years), receiving pelvic radiation therapy (2 Gyx23-25 fractions in 5 weeks) were included. Serum testosterone, FSH and LH were determined before start of treatment, at the 10th and 25th fractions, and 4-6 weeks after completed radiotherapy. The testicular dose was determined by thermoluminescent dosimetry. RESULTS: Five weeks of radiation therapy (46-50 Gy) resulted in a 100% increase in serum FSH, a 70% increase in LH, and a 25% reduction in testosterone levels. After treatment, 35% of the patients had serum testosterone levels below lower limit of reference. The mean radiation dose to the testicles was 8.4 Gy. A reduction in testosterone values was observed already after a mean dose of 3.3 Gy (10th fraction). CONCLUSION: Radiation therapy (46-50 Gy) for rectal cancer resulted in a significant increase in serum FSH and LH and a significant decrease in testosterone levels, indicating that sex hormone production is sensitive to radiation exposure in patients with a mean age of 65 years.