Disruption of parity-induced tumor suppressor pathways by xenoestrogen exposures
Breast Cancer & the Environment Research Program
University of Massachusetts, Amherst
University of Massachusetts Medical School - Baystate Health
NIEHS Grant: U01ES26140
Other Community and Academic Partners:
UMass Center for Clinical and Translational Science
The Rays of Hope Center for Breast Cancer Research
Girls Inc. of Holyoke
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 (benzophenones, 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, researchers are testing four 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 whether xenoestrogens interfere with the effects of pregnancy on critical tumor suppressor pathways.
Researchers 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 are used to confirm responses and define subsets of women who are highly sensitive or resistant to xenoestrogens. They then compare effects of xenoestrogens in explant cultures of breast tissue and in BALB/c mice. 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. Researchers also are testing the effects of xenoestrogens on tumorigenesis. The ability of xenoestrogens to cause progression of premalignant cells is 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.
The Community Partners provide a means to communicate dynamically 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.