Environmental and commercially prevalent estrogenic compounds (xenoestrogens) have been classified as endocrine disruptors, or agents capable of disrupting normal hormone function in the human body. Exposure to xenoestrogens has been shown to result in diverse biological outcomes, such as infertility and developmental defects. Although considerable effort has been directed toward delineating the effect of xenoestrogens on the female reproductive system, few studies have examined the effect of such agents on growth and maintenance of the prostate gland. Prostatic epithelia and the cells of primary prostatic adenocarcinomas are dependent on androgen for proliferation and survival. This critical dependence of the prostate on androgen is exploited in the treatment of prostatic proliferative diseases (e.g. benign prostatic hyperplasia and prostatic adenocarcinoma). Increasing evidence also demonstrates a role for estrogen in the prostate cell proliferation. For example, exposure to estrogen has been shown to directly induce prostate hyperplasia animal model systems. Additionally, the anti-estrogen Tamoxifen is used clinically to reduce prostate growth. Despite these observations, the mechanism by which estrogen stimulates prostate cell growth has not been determined. Moreover, the effect of xenoestrogens on prostate proliferation and growth has not been explored. Here we show that the xenoestrogen bis-phenol A (BPA) provides inappropriate mitogenic stimuli to prostatic epithelial cells. This mitogenic activity is associated with nuclear receptor activity, and allows prostate cells to bypass their requirement for androgen. Based on our preliminary data, we hypothesize that BPA activates specific nuclear receptors in prostate cells to propagate inappropriate mitogenic signaling pathways and initiate cellular proliferation. This action of BPA likely facilitates the development of prostate hyperplasias and neoplasias. The experiments outlined herein will determine the mechanism by which BPA activates nuclear receptors in prostate epithelia, define the mitogenic signaling pathway for BPA in this cell type, and assess the influence of these agents on the formation and treatment of prostate hyperplasias and neoplasias.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093404-02
Application #
6620290
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2003-04-15
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$250,759
Indirect Cost
Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Keri, Ruth A; Ho, Shuk-Mei; Hunt, Patricia A et al. (2007) An evaluation of evidence for the carcinogenic activity of bisphenol A. Reprod Toxicol 24:240-52
Burd, Craig J; Petre, Christin E; Morey, Lisa M et al. (2006) Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation. Proc Natl Acad Sci U S A 103:2190-5
Hess-Wilson, Janet K; Daly, Hannah K; Zagorski, William A et al. (2006) Mitogenic action of the androgen receptor sensitizes prostate cancer cells to taxane-based cytotoxic insult. Cancer Res 66:11998-2008
Hess-Wilson, J K; Boldison, J; Weaver, K E et al. (2006) Xenoestrogen action in breast cancer: impact on ER-dependent transcription and mitogenesis. Breast Cancer Res Treat 96:279-92
Knudsen, Erik S; Knudsen, Karen E (2006) Retinoblastoma tumor suppressor: where cancer meets the cell cycle. Exp Biol Med (Maywood) 231:1271-81
Wetherill, Yelena B; Hess-Wilson, Janet K; Comstock, Clay E S et al. (2006) Bisphenol A facilitates bypass of androgen ablation therapy in prostate cancer. Mol Cancer Ther 5:3181-90
Wetherill, Yelena B; Fisher, Nicola L; Staubach, Ann et al. (2005) Xenoestrogen action in prostate cancer: pleiotropic effects dependent on androgen receptor status. Cancer Res 65:54-65
Barnes-Ellerbe, Sonya; Knudsen, Karen E; Puga, Alvaro (2004) 2,3,7,8-Tetrachlorodibenzo-p-dioxin blocks androgen-dependent cell proliferation of LNCaP cells through modulation of pRB phosphorylation. Mol Pharmacol 66:502-11
Wetherill, Yelena B; Petre, Christin E; Monk, Kelly R et al. (2002) The xenoestrogen bisphenol A induces inappropriate androgen receptor activation and mitogenesis in prostatic adenocarcinoma cells. Mol Cancer Ther 1:515-24