Abstract

A woman's overall lifetime exposure to estrogen is a critical risk factor for the development of breast cancer. A number of environmental compounds, termed endocrine disrupting compounds (EDCs) have been shown to bind and activate the estrogen receptor and are thus implicated in breast cancer tumorigenesis. However, it has become clear that EDC activation of the estrogen receptor induces ligand-specific transcriptional programs. It is our hypothesis that chromatin structure is a key regulator of endocrine, disruptor action in breast cancer development and progression. In this proposal, we will use an unbiased genomic approach to characterize chromatin structure in breast cancer cells following treatment with bisphenol A and genistein. EDC responsive regions will be characterized for chromatin modifications and nucleosome positioning. Finally, the effects of long term exposure to both bisphenol A and genistein on estrogen receptor recruitment will be examined. These studies will clarify the mechanisms by which EDCs elicit specific transcriptional profiles in the breast.

Public Health Relevance

This proposed work aims to identify mechanisms by which EDCs generate specific transcriptional programs. It will thus provide the necessary infomiation to help predict the risks associated with exposure and identify potential markers of high risk individuals.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Transition Award (R00)
Project #
4R00ES019918-02
Application #
8607255
Study Section
Special Emphasis Panel (NSS)
Program Officer
Reinlib, Leslie J
Project Start
2013-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$249,000
Indirect Cost
$86,520

  Institution

Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210

  Publications

Hindman, Andrea R; Mo, Xiaokui Molly; Helber, Hannah L et al. (2017) Varying Susceptibility of the Female Mammary Gland to In Utero Windows of BPA Exposure. Endocrinology 158:3435-3447
Young, Nicholas A; Valiente, Giancarlo R; Hampton, Jeffrey M et al. (2017) Estrogen-regulated STAT1 activation promotes TLR8 expression to facilitate signaling via microRNA-21 in systemic lupus erythematosus. Clin Immunol 176:12-22
Patterson, Andrea R; Mo, Xiaokui; Shapiro, Ali et al. (2015) Sustained reprogramming of the estrogen response after chronic exposure to endocrine disruptors. Mol Endocrinol 29:384-95
Young, Nicholas A; Wu, Lai-Chu; Burd, Craig J et al. (2014) Estrogen modulation of endosome-associated toll-like receptor 8: an IFN?-independent mechanism of sex-bias in systemic lupus erythematosus. Clin Immunol 151:66-77
Burd, Craig J; Archer, Trevor K (2013) Chromatin architecture defines the glucocorticoid response. Mol Cell Endocrinol 380:25-31