Poster abstracts

Poster number 82 submitted by Andrea R. Hindman

Mesenchymal reprogramming and altered density in the mammary gland following in utero bisphenol A exposure

Andrea R. Hindman (Molecular, Cellular & Developmental Biology Program, Dept. of Molecular Genetics, The James Comprehensive Cancer Center), Xiaokui Molly Mo (Center for Biostatistics, Ohio State University Wexner Medical Center), Hannah L. Helber (Dept. of Molecular Genetics ), Claire E. Kovalchin (Life Sciences Education), Nanditha Ravichandran (Dept. of Molecular Genetics), Kyle Voytovich (Data Analytics)

Abstract:
The treatment of pregnant women in the 1940’s with the synthetic estrogen, diethylstilbestrol (DES), demonstrated that in utero exposures to estrogenic compounds, collectively known as endocrine disrupting compounds (EDCs), is linked to increased risk for later-life development of breast, uterine and cervical cancers. While pregnant women are no longer prescribed synthetic estrogens, significant evidence suggests that early-life exposure to a known EDC, bisphenol A (BPA), may initiate similar consequences. It is believed that activation of the estrogen receptor (ER) is critical for this pathogenesis, though the molecular mechanisms remain undefined. We utilized an in utero model to characterize the effects of BPA on mammary gland development. ERα expression was demonstrated to be strictly mesenchymal during early mammary placode formation despite evidence of epithelial defects in BPA-treated adult mammary glands. The gap between mesenchymal ER expression and later-life epithelial defects led us to examine varied exposures to in utero BPA. We found that the period during which the mammary placode is completely surrounded by the ERα-positive mesenchyme was observed to be the most susceptible to early-life BPA exposure. Both stromal proliferation and ERα expression correlated to early epithelial growth. Gene expression and DNA methylation analyses of isolated adult mammary fibroblast, luminal and basal epithelial cell populations demonstrated cell type-specific effects of in utero BPA; supporting an epigenetic program. Interestingly, extracellular matrix signaling was a pathway significantly altered by BPA; breast density is one of the greatest risk factors for breast cancer. Our work suggests a model by which mammary defects caused by in utero BPA results in reprogramming of the stroma distinct from epithelial cells. Later-life defects in the epithelia may be a result of altered mesenchymal paracrine signals. Our analysis is the first of its kind to investigate alterations in the component cell populations of the mammary gland following in utero exposure to BPA and define the permanent epigenetic changes in the adult tissue. Our findings can inform analysis of human populations, determining the mechanisms of deregulation that contribute to later-life risk.

References:
1. (NIH) NIH. DES Research Update 1999: current knowledge, future directions. 1999 Contract No.: U.S. Dep. Health Hum. Serv.
2. Weber Lozada K, Keri RA. Bisphenol A increases mammary cancer risk in two distinct mouse models of breast cancer. Biol Reprod. 2011;85(3):490-497.
3. Boyd NF, Martin LJ, Stone J, Greenberg C, Minkin S, Yaffe MJ. Mammographic densities as a marker of human breast cancer risk and their use in chemoprevention. Curr Oncol Rep. 2001;3:314–321.
4. Provenzano PP, Inman DR, Eliceriri KW, Knittel JG, Yan L, Rueden CT, White JG and Keely PJ. Collagen density promotes mammary tumor initiation and progression. BMC Med. 2008; 6:11.
5. Provenzano PP, Eliceiri KW, Campbell JM, InMan DR, White JG and Kelly PJ. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 2006; 4:38.

Keywords: endocrine disruption, bisphenol A, epigenetic