Increasing evidence indicates that cancer can start before birth. In utero exposure to hormonal disruptor diethylstilbestrol (DES) has been associated with increased breast cancer risk in later life by unknown mechanisms. BPA is a common environmental chemical with estrogenic properties. Perinatal exposure to BPA associated breast cancer risk is emerging as a serious health concern. Previous studies using carcinogen models indicate that perinatal exposure to BPA induces proestrogenic effect in early adult stage and promotes mammary tumor development in these animals, but detailed mechanisms of these effects remain unclear. We have been studying hormonal modulation of erbB-2 mediated breast cancer risk using the MMTV-erbB-2 transgenic model. We demonstrated that in utero exposure to hormonal disruptor genistein or BPA promoted mammary tumor development in later life, which was preceded with significantly altered histoarchitectures and signaling in both estrogen receptor (ER) and erbB-2 pathways in the adult glands. Our data also suggest that in utero exposure to hormonal disruptors may induce the repopulation of mammary stem/progenitor cells. To investigate the molecular mechanisms of in utero exposure to BPA associated mammary tumor risk, we hypothesize that in utero exposure to BPA increase mammary cancer risk of erbB-2 transgenic mice through the induction of ER-erbB-2 crosstalk and the reprogramming of mammary stem cells.
The specific aims are: 1) To investigate in utero exposure to BPA induced activation of erbB-2 pathway and the crosstalk between ER and erbB-2 pathways. Modification of ER-DNA binding patterns will be analyzed using functional genomics. 2). To determine the effect of in utero exposure to BPA on the reprogramming of mammary stem/progenitor cells by flow cytometry analysis of stem cell markers and mammary gland transplantation. With this clinically relevant mouse model and novel approaches, the results from this project are expected to have significant impact on breast cancer prevention and management.

Public Health Relevance

This project aims to study the mechanisms of in utero exposure to bisphenol A (IUE/BPA) on mammary tumor risk in erbB-2 transgenic mice. We focus on IUE/BPA induced ER-erbB-2 crosstalk, genome-wide ER-DNA binding and mammary stem cell reprogramming. The results are expected to have profound impact on in utero exposure to endocrine disrupting compound (EDC)-associated breast cancer risk later in life.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory/Developmental Grants (R21)
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Cancer Etiology Study Section (CE)
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Reinlib, Leslie J
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North Carolina Central University
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Howard, Erin W; Yang, Xiaohe (2018) microRNA Regulation in Estrogen Receptor-Positive Breast Cancer and Endocrine Therapy. Biol Proced Online 20:17
Lee, Harry; Saini, Nipun; Howard, Erin W et al. (2018) Ganetespib targets multiple levels of the receptor tyrosine kinase signaling cascade and preferentially inhibits ErbB2-overexpressing breast cancer cells. Sci Rep 8:6829
Ma, Zhikun; Parris, Amanda B; Howard, Erin W et al. (2018) Caloric restriction inhibits mammary tumorigenesis in MMTV-ErbB2 transgenic mice through the suppression of ER and ErbB2 pathways and inhibition of epithelial cell stemness in premalignant mammary tissues. Carcinogenesis 39:1264-1273
Ma, Zhikun; Kim, Young Mi; Howard, Erin W et al. (2018) DMBA promotes ErbB2?mediated carcinogenesis via ErbB2 and estrogen receptor pathway activation and genomic instability. Oncol Rep 40:1632-1640
Zhao, Ming; Howard, Erin W; Parris, Amanda B et al. (2017) Alcohol promotes migration and invasion of triple-negative breast cancer cells through activation of p38 MAPK and JNK. Mol Carcinog 56:849-862
Zhao, Qingxia; Parris, Amanda B; Howard, Erin W et al. (2017) FGFR inhibitor, AZD4547, impedes the stemness of mammary epithelial cells in the premalignant tissues of MMTV-ErbB2 transgenic mice. Sci Rep 7:11306
Lee, Harry; Saini, Nipun; Parris, Amanda B et al. (2017) Ganetespib induces G2/M cell cycle arrest and apoptosis in gastric cancer cells through targeting of receptor tyrosine kinase signaling. Int J Oncol 51:967-974
Parris, Amanda B; Zhao, Qingxia; Howard, Erin W et al. (2017) Buformin inhibits the stemness of erbB-2-overexpressing breast cancer cells and premalignant mammary tissues of MMTV-erbB-2 transgenic mice. J Exp Clin Cancer Res 36:28
Zhao, Ming; Howard, Erin W; Parris, Amanda B et al. (2017) Activation of cancerous inhibitor of PP2A (CIP2A) contributes to lapatinib resistance through induction of CIP2A-Akt feedback loop in ErbB2-positive breast cancer cells. Oncotarget 8:58847-58864
Ma, Zhikun; Parris, Amanda B; Xiao, Zhengzheng et al. (2017) Short-term early exposure to lapatinib confers lifelong protection from mammary tumor development in MMTV-erbB-2 transgenic mice. J Exp Clin Cancer Res 36:6

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