Maternal Dioxin Exposure Combined with a Diet High in Fat Increases Mammary Cancer Incidence in Mice

BackgroundRESULTS from previous studies have suggested that breast cancer risk correlates with total lifetime exposure to estrogens and that early-life 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or diets high in fat can also increase cancer risk.ObjectivesBecause both TCDD and diet affect the estrogen pathway, we examined how TCDD and a high-fat diet (HFD) interact to alter breast cancer susceptibility.MethodsWe exposed pregnant female FVB/NJ mice (12.5 days postcoitus) to 1 microg/kg TCDD or vehicle; at parturition, the dams were randomly assigned to a low-fat diet (LFD) or a high-fat diet (HFD). Female offspring were maintained on the same diets after weaning and were exposed to 7,12-dimethylbenz[a]anthracene on postnatal days (PNDs) 35, 49, and 63 to initiate mammary tumors. A second cohort of females was treated identically until PND35 or PND49, when mammary gland morphology was examined, or PND50, when mammary gland mRNA was analyzed.ResultsWe found that maternal TCDD exposure doubled mammary tumor incidence only in mice fed the HFD. Among HFD-fed mice, maternal TCDD exposure caused rapid mammary development with increased Cyp1b1 (cytochrome P450 1B1) expression and decreased Comt (catechol-O-methyltransferase) expression in mammary tissue. Maternal TCDD exposure also increased mammary tumor Cyp1b1 expression.ConclusionsOur data suggest that the HFD increases sensitivity to maternal TCDD exposure, resulting in increased breast cancer incidence, by changing metabolism capability. These results provide a mechanism to explain epidemiological data linking early-life TCDD exposure and diets high in fat to increased risk for breast cancer in humans

Role of dietary fatty acids in mammary gland development and breast cancer

Breast cancer is the most common cancer among women worldwide. Estimates suggest up to 35% of cases may be preventable through diet and lifestyle modification. Growing research on the role of fats in human health suggests that early exposure in life to specific fatty acids, when tissues are particularly sensitive to their environment, can have long-term health impacts. The present review examines the role of dietary fat in mammary gland development and breast cancer throughout the lifecycle. Overall, n-3 polyunsaturated fatty acids have promising cancer-preventive effects when introduced early in life, and warrant further research to elucidate the mechanisms of action

Body fatness during childhood and adolescence and incidence of breast cancer in premenopausal women: a prospective cohort study

INTRODUCTION: Body mass index (BMI) during adulthood is inversely related to the incidence of premenopausal breast cancer, but the role of body fatness earlier in life is less clear. We examined prospectively the relation between body fatness during childhood and adolescence and the incidence of breast cancer in premenopausal women. METHODS: Participants were 109,267 premenopausal women in the Nurses' Health Study II who recalled their body fatness at ages 5, 10 and 20 years using a validated 9-level figure drawing. Over 12 years of follow up, 1318 incident cases of breast cancer were identified. Cox proportional hazards regression was used to compute relative risks (RRs) and 95% confidence intervals (CIs) for body fatness at each age and for average childhood (ages 5–10 years) and adolescent (ages 10–20 years) fatness. RESULTS: Body fatness at each age was inversely associated with premenopausal breast cancer incidence; the multivariate RRs were 0.48 (95% CI 0.35–0.55) and 0.57 (95% CI 0.39–0.83) for the most overweight compared with the most lean in childhood and adolescence, respectively (P for trend < 0.0001). The association for childhood body fatness was only slightly attenuated after adjustment for later BMI, with a multivariate RR of 0.52 (95% CI 0.38–0.71) for the most overweight compared with the most lean (P for trend = 0.001). Adjustment for menstrual cycle characteristics had little impact on the association. CONCLUSION: Greater body fatness during childhood and adolescence is associated with reduced incidence of premenopausal breast cancer, independent of adult BMI and menstrual cycle characteristics

Body silhouette, menstrual function at adolescence and breast cancer risk in the E3N cohort study

We analysed the relation between adult breast cancer risk and adiposity in ages 8–25, and among 90 509 women included in the E3N cohort study, and investigated the potential modification effect of certain factors. Participants completed a questionnaire that included a set of eight silhouettes corresponding to body shape at different ages. During the follow-up (mean=11.4 years), 3491 breast cancer cases were identified. Negative trends in risk of breast cancer with increasing body silhouettes at age 8 and at menarche were observed, irrespective of menopausal status, with relative risks of 0.73 (0.53–0.99) and 0.82 (0.66–1.02) for women who reported a silhouette equal or greater than the fifth silhouette at age 8 and at menarche, respectively. We observed no clear effect modification by age at menarche, delay between age at menarche, regular cycling, regularity of cycles in adult life or body mass index at baseline

Intrauterine environments and breast cancer risk: meta-analysis and systematic review

INTRODUCTION: Various perinatal factors, including birth weight, birth order, maternal age, gestational age, twin status, and parental smoking, have been postulated to affect breast cancer risk in daughters by altering the hormonal environment of the developing fetal mammary glands. Despite ample biologic plausibility, epidemiologic studies to date have yielded conflicting results. We investigated the associations between perinatal factors and subsequent breast cancer risk through meta-analyses. METHODS: We reviewed breast cancer studies published from January 1966 to February 2007 that included data on birth weight, birth order, maternal age, gestational age, twin status, and maternal or paternal smoking. Meta-analyses using random effect models were employed to summarize the results. RESULTS: We found that heavier birth weights were associated with increased breast cancer risk, with studies involving five categories of birth weight identifying odds ratios (ORs) of 1.24 (95% confidence interval [CI] 1.04 to 1.48) for 4,000 g or more and 1.15 (95% CI 1.04 to 1.26) for 3,500 g to 3,999 g, relative to a birth weight of 2,500 to 2,599 g. These studies provided no support for a J-shaped relationship of birthweight to risk. Support for an association with birthweight was also derived from studies based on three birth weight categories (OR 1.15 [95% CI 1.01 to 1.31] for > or =4,000 g relative to or =3,000 g relative to <3,000 g). Women born to older mothers and twins were also at some increased risk, but the results were heterogeneous across studies and publication years. Birth order, prematurity, and maternal smoking were unrelated to breast cancer risk. CONCLUSION: Our findings provide some support for the hypothesis that in utero exposures reflective of higher endogenous hormone levels could affect risk for development of breast cancer in adulthood

Environmental exposures and mammary gland development: state of the science, public health implications, and research recommendations.

ObjectivesPerturbations in mammary gland (MG) development may increase risk for later adverse effects, including lactation impairment, gynecomastia (in males), and breast cancer. Animal studies indicate that exposure to hormonally active agents leads to this type of developmental effect and related later life susceptibilities. In this review we describe current science, public health issues, and research recommendations for evaluating MG development.Data sourcesThe Mammary Gland Evaluation and Risk Assessment Workshop was convened in Oakland, California, USA, 16-17 November 2009, to integrate the expertise and perspectives of scientists, risk assessors, and public health advocates. Interviews were conducted with 18 experts, and seven laboratories conducted an MG slide evaluation exercise. Workshop participants discussed effects of gestational and early life exposures to hormonally active agents on MG development, the relationship of these developmental effects to lactation and cancer, the relative sensitivity of MG and other developmental end points, the relevance of animal models to humans, and methods for evaluating MG effects.SynthesisNormal MG development and MG carcinogenesis demonstrate temporal, morphological, and mechanistic similarities among test animal species and humans. Diverse chemicals, including many not considered primarily estrogenic, alter MG development in rodents. Inconsistent reporting methods hinder comparison across studies, and relationships between altered development and effects on lactation or carcinogenesis are still being defined. In some studies, altered MG development is the most sensitive endocrine end point.ConclusionsEarly life environmental exposures can alter MG development, disrupt lactation, and increase susceptibility to breast cancer. Assessment of MG development should be incorporated in chemical test guidelines and risk assessment