Consortium Membership

Puberty and young adulthood are periods of high susceptibility to environmental and life style factors that increase breast cancer risk. We intend to identify how a high animal fat diet (HFD) consumed during puberty or young adulthood increases breast cancer risk. Ovarian hormones are implicated in the etiology of breast cancer. Estrogenic endocrine disrupting chemicals (EDCs) may act as agonists or antagonists during mammary gland development and mammary tumorigenesis, and should be studied to evaluate their potential in promoting breast cancer. We will study the interaction of HFD with a widely used but understudied EDC, oxybenzone (benzophenone-3, BP-3)–a common ingredient in sunscreen and other personal use products, to affect breast cancer risk. Using a transdisciplinary approach, findings in mice will be translated to humans to identify predictive biomarkers for risk and intervention strategies to reduce that risk. Recently, HFD was shown to increase premenopausal breast cancer risk in normal weight, but not overweight, young women. This agrees with our published and preliminary studies identifying both pubertal and adult windows of susceptibility (WOS) to the promotional effects of HFD in obesity-resistant BALB/c mice. Of note, HFD promoted basal- like breast cancer, which also predominantly occurs in young women. The pubertal WOS for HFD tumor promotion indicates potential efficacy of early age preventative intervention to reduce adult breast cancer risk. This project will: 1) Determine, under low fat diet (LFD) and HFD, BP-3 dosages in mice corresponding to human low spring/fall and high summer exposure urine levels, and then assess BP-3 effects on pubertal mammary gland development and adult morphology, body weight, and reproductive parameters relevant to the action of BP-3 as an EDC; 2) Determine BP-3 effects on mammary tumor susceptibility in two mouse breast cancer models (p53-null and TIP30-null transplant BALB/c mice) fed HFD vs. LFD, and identify pubertal vs. adult intermediate biomarkers, focusing on inflammatory and proliferative processes associated with tumorigenesis; 3) Test interventions against immune cells and growth factor pathways to alter intermediate biomarkers and ultimately reduce mammary tumorigenesis; 4) Analyze a human young adult female established cohort for the relationship(s) among intermediate serum biomarkers, HFD, BMI, and BP-3 exposure that may be predictive of increased premenopausal breast cancer risk; 5) Researchers will interact regularly with a Breast Cancer Advocate Advisory Board to receive input about the research directions, addressing concerns of affected communities. Research will be translated for education and risk reduction messages, disseminated in collaboration with MSU Extension, and message efficacy will be assessed by communication scientists. These studies will elucidate mechanisms linking HFD and an EDC with proliferative and immune biomarkers of breast cancer risk and identify strategies for early prevention and intervention to reduce breast cancer, particularly basal-like mammary cancer for which approaches to intervention are limited.

Accumulating human and animal data support the hypothesis that breast cancer risk is modified during key windows of susceptibility. These include the prenatal and pregnancy windows, during which time the breast changes in structure and function and breast cells rapidly proliferate. The Columbia Center for Children’s Environmental Health (CCCEH) birth cohort is one of the few cohorts in the world with extensive biospecimens and environmental monitoring data that are reflective of the contemporary environment collected during the pregnancy time period for mothers and during the prenatal period for children. In addition to multiple samples of urine throughout pregnancy and blood at the time of delivery, mothers wore a small backpack containing a personal ambient air monitor during the daytime hours for several days to measure personal air pollution exposures. The cohort is comprised exclusively of Hispanic Dominican and African-American women residing in New York City and their children, who were born in the Bronx or Northern Manhattan between 1998 and 2006 (N=543 mothers of whom 52.5% (N=285) are mother-daughter dyads). These families reflect our local community, as well as represent the population subgroups experiencing a rapidly increasing breast cancer incidence in young women. We propose to build on this unique birth cohort specifically by measuring breast tissue characteristics and breast density, a strong intermediate marker of breast cancer risk through optical spectroscopy (OS) for all mothers and daughters and mammography for mothers over 40 years of age (Project 1). We will collect clinical measures of breast tissue characteristics, anthropometry and biospecimens in the now adolescent girls (age range 10-16 years) and their mothers. There are few human studies in which exposures to the same pollutants have been measured to allow for simultaneous evaluation of their effect on both the mother’s breast cancer risk and that of her daughter. We will focus on Polycyclic Aromatic Hydrocarbons (PAH), by-products of combustion classified as possible carcinogens by IARC and the US EPA. We will couple our human study with robust animal experiments investigating the role of airborne PAH during gestation on altered mammary tissue and systemic DNA methylation and expression of genes important to DNA repair and apoptosis in mothers, their offspring, and their grand offspring (Project 2). We also will investigate the role of PAH on PPAR gene regulation, a gene important to lipid metabolism and associated with breast cancer risk, as well as examine mammary tissue alterations in both the animal and human models and compare genes that are methylated in humans with higher PAH exposure across both model systems. Project 3 ties together both projects by building on the CCCEH Community Outreach and Translation Core to integrate our research findings with messages about environmental exposures and breast cancer prevention in our study participants and larger community in our Herbert Irving Comprehensive Cancer Center (HICCC) and Columbia University catchment area.

Sporadic breast cancer is a hormone dependent malignancy with a steadily increasing incidence. Although the reasons for this increase are uncertain, epidemiologic findings support an important role for environmental pollutants containing endocrine disrupting chemicals (EDCs) and their metabolites. The last six decades have witnessed a massive introduction of hormonally active synthetic chemicals into the environment. Therefore, exposure to EDCs at critical windows of opportunity during the lifecourse may play a role in changing the susceptibility to breast carcinogenesis. Herein, we propose to explore whether exposure to three environmental compounds with different endocrine-disrupting pathways, butyl perfluorooctanoic acid (PFOA), benzyl phthalate (BBP), and Zeranol during the pubertal period will alter breast composition and/or the susceptibility to breast cancer. We will build on an existing puberty cohort of in 400 Latino girls in Chile for whom breast composition measurements at Tanner stage 4 are already available. We propose to extend this cohort to add a breast composition assessment two years after menarche as breast density tracks from this point into adulthood. We propose to study the influence of the three chemicals, PFOA, BBP, and Zeranol, individually and in combination, on breast composition in these Latino girls. To explore whether pubertal exposure to PFOA, BBP, and Zeranol has deleterious effects on mammary gland biology and susceptibility to carcinogenesis, we will study the morphology, transcriptome, and tumorigenesis of the rat mammary gland exposed to these compounds. Results from our work will be disseminated via community outreach to family members of study participants and community members in Chile. Furthermore, we will connect this project and BCERP with breast cancer advocacy in the United States, creating opportunities for translation into personal and policy change to promote health.

Residents in medically underserved areas of Washington, DC have express the concern that the high incidence of cancer in their community is due to contaminants in their food and water, including metals. Results from our laboratory and others show that environmentally relevant amounts of specific metals and metalloids, referred to as metalloestrogens, activate estrogen receptor-alpha (ERa) in vitro and in vivo through a high affinity interaction with the ligand binding domain (LBD) of the receptor. These metals and metalloids fall into two separate subclasses, bivalent cations and oxyanions. New results from our laboratory suggest that metalloestrogens also activate progesterone receptor-B (PR-B). The ability to activate ERa, and potentially PR-B suggests that environmental exposure to metals and metalloids with estrogen- and progestin-like activity may increase the risk of developing breast cancer. In response to the concerns of the community, this application will address the question whether exposure to metals and metalloids increases the risk of developing breast cancer by testing the hypothesis that higher lifetime environmental exposure to metals and metalloids with estrogen- and progesterone-like activity is associated with higher mammographic density in women during the menopausal transition and delays or reduces the involution of mammary gland and the decline in mammographic breast density during this period. Aim 1 will determine whether metals and metalloids mimic the effects of estrogens and progestin on mammary gland morphology, stem and progenitor cells, and gene expression in a menopausal animal model (Aim 1a) and define the mechanisms by which metals and metalloids activate PR-B in in vitro assays (Aim 1b). Aim 2 will determine whether environmental exposure to metallohormones is associated with changes in breast density through the menopausal transition and define the mechanism by which metals and metalloids alter breast density. Specifically, Aim 2 will establish if: a, higher metallohormone levels are associated with increased mammographic density; b, higher metallohormone levels are associated with maintenance of higher breast density through the menopausal transition; and c, polymorphisms in the calcium pathway are associated with increased mammographic breast density indicating the mechanism through which bivalent cationic metallohormones increase risk. To accomplish these aims, we will continue to engage with our partners to get their input, to help collect data, and to translate and communicate the scientific findings to the community.

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There is substantial evidence suggesting that environmental disrupting chemicals (EDCs) initiate and promote the development of breast cancer. In this U01 application, we will study an under-investigated window of susceptibility for exposure: the menopausal transition. This transition begins when ovarian function begins to decline and ends at menopause when there is a cessation of ovarian function resulting in low levels of estrogens. During this important window of susceptibility, the Womens’ Health Initiative (WHI) reported that hormone therapy increased both the incidence of and mortality from breast cancer. The WHI results are explained by a biologically-based breast tumor model; it suggests that hormone therapy in the menopausal transition promotes the growth of pre-existing occult lesions and minimally initiated de novo tumors. We hypothesize that EDCs mimic hormone therapy and promote the development of breast cancer during the menopausal transition. We will focus on polybrominated diphenyl ethers (PBDEs) because of their persistence in the environment and human tissue and on bisphenol A (BPA) because of its widespread use in food-grade plastics and thermal paper. Both EDCs are recognized as major health concerns. Our proposed research will allow us to evaluate the role of these EDCs, individually and combined, on the development of breast cancer during the menopausal transition. To determine the mechanisms, we will apply a transdisciplinary approach using cell culture, samples collected from women during the menopausal transition, and mouse models. In Specific Aim 1, we will determine the biologic actions and mechanisms of EDCs, singly and in combination, using the AroER-Tri screen cell culture system developed by the joint-PI, Dr. Chen. In Specific Aim 2, we will assess the effects of EDCs in women during the menopausal transition on estrogenic activity and the epigenome, as well as the association of the EDCs and breast cancer. In Specific Aim 3, we will test the effects of these EDCs on the development of mammary lesions in a mouse model of menopause, and compare to the effects in an ovarectomized mouse model. Our transdisciplinary approach will capitalize on the strengths of each study type and allow us to conduct a more comprehensive assessment than any single approach. This is possible because of our experienced, multidisciplinary team. In Specific Aim 4, with our community partners, we will provide a one-stop web- based resource for evidence-based materials on the role of environmental exposures and development of breast cancer, particularly during the menopausal transition. Furthermore, we will develop, test, and disseminate educational materials to multi-culturally diverse communities. We will share our expertise/work with other multi-disciplinary teams in the BCERP to produce valuable results and increase the amount of relevant scientific knowledge on the mechanisms and effects of EDC exposure. We expect this work to result in future prevention strategies to reduce or mitigate exposures and promote effective communication of scientifically sound findings to the general public and policy makers.

Parity engages pathways within the breast epithelium that render it resistant to carcinogenesis. These pathways are potent as parity reduces the risk associated with carcinogens and inherited risk alleles preventing as many as 70,000 cases of breast cancer annually. The levels of estrogens during pregnancy are sufficient to mimic the protective effects of parity. The actions of estrogens are mediated by two estrogen receptor subtypes (ERα and ERβ) that balance their competing effects on proliferation and growth suppression mediated by the p53 tumor suppressor pathway. Pregnancy also suppresses WNT/ β-catenin signaling and reduces the pool of vulnerable stem cells within the mammary epithelium. However, chronic exposure to exogenous estrogens erodes the protective effects of pregnancy in rodents. During pregnancy, women are exposed to high levels of xenoestrogens (bensophenones, parabens, phthalates) that differ in their potencies for ERα and ERβ. Therefore, pregnancy is a critical window during which xenoestrogens may disrupt tumor suppressor pathways and render the breast epithelium susceptible to carcinogenesis. In these experiments, we will test 4 xenoestrogens that are abundant in pregnant women and differ in potency for ERα and ERβ. Parallel experiments in primary breast tissues and mouse models are used to determine if xenoestrogens interfere with the effects of pregnancy on critical tumor suppressor pathways. Specific Aim 1 will use breast epithelial cells to determine the effects of xenoestrogens on tumor suppressor pathways and the variation in responses among women. Dose-response relationships for each xenoestrogen will be determined in MCF-7 breast cancer cells expressing either ERα or both ERα+ERβ. Primary cultures of normal breast epithelial cells will be used to confirm responses and define subsets of women who are highly sensitive or resistant to xenoestrogens. Specific Aim 2 compares effects of xenoestrogens in explant cultures of breast tissue and in BALB/c mice. Primary breast explants more faithfully reflect signaling within breast tissue and complement results from Aim 1. Parallel treatments in mice that are particularly sensitive to estrogens (BALB/c) will validate the in vivo model and determine effects of chronic exposures to xenoestrogens on tumor suppressor pathways. Specific Aim 3 will test the effects of xenoestrogens on tumorigenesis. The ability of xenoestrogens to cause progression of premalignant cells will be tested using transplants of CDβGeo cells. The ability of xenoestrogens to reverse the protective effect of parity will be tested in mice bearing transplants of Trp53+/- mammary epithelium. Community Engagement: The Community Partners provide a means to dynamically communicate the concerns of the community and results from research. Importantly, the experiments are designed to identify a subset of women who may be especially vulnerable to xenoestrogens and demonstrate the relevance of the mouse models to human exposures.

The critical need remains to improve our ability to prevent breast cancer. An area of research that holds great promise for reducing breast cancer risk concerns improving our knowledge of the impact of environmental factors, especially when these factors appear to act when the breast is particularly susceptible to changes that ultimately lead to cancer. The proposed Coordinating Center for the Breast Cancer and the Environment Research Program (BCERP) consortium will support research that follows national recommendations to prioritize prevention, use transdisciplinary research approaches, and intensify the study of chemical and physical factors that potentially influence the risk of developing breast cancer. Our overarching goal is to support integrated scientific research to enhance our understanding of environmental and genetic factors underlying breast cancer risk throughout the lifespan, with particular focus on windows of susceptibility. Specific Aims are: 1-to provide leadership in team science by identifying opportunities to facilitate cross-project transdisciplinary interaction, standardize and integrate research efforts, and maximize use of resources; 2-to provide exceptional coordination for the consortium including defining a shared vision and mission, identifying shared resources, developing standard policies, managing Opportunity Funds to distribute to Consortium members, assisting NIH staff, and supporting a Steering Committee, Working Groups, and an annual scientific meeting; 3-to leverage sharing of data and other resources among BCERP members; 4- to support cross-project communication as well as dissemination of findings to diverse partners and audiences including the broader breast cancer and environmental science research communities, and to support the training and mentoring of the next generation of breast cancer researchers; and 5-to facilitate internal and external evaluation to maximize the Coordinating Center’s and Consortium’s performance, transdisciplinary nature, productivity and effectiveness. Our mission is to provide intellectual leadership and logistical support for the BCERP consortium by identifying and facilitating opportunities for cross-BCERP collaboration, and disseminating research findings through partnerships with stakeholders. Our multidisciplinary team includes experts in breast cancer epidemiology, basic science, environmental health, toxicology, program evaluation, biostatistics, outreach/community engagement, and research administration, as well as mentoring and training. The University of Wisconsin Carbone Cancer Center provides the ideal environment for supporting the Coordinating Center due to its multiple resources and strong established relationships with local, regional, and national research and advocacy organizations. The BCERP Coordinating Center will use multiple innovative approaches to leverage Consortium members’ common passion for elucidating the role of environmental factors that act during windows of susceptibility to increase risk of breast cancer, provide opportunities for collaboration, and enable BCERP to bring about substantive reductions in the burden of this common disease.