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PLEIOTROPIC EFFECTS OF XENOESTROGEN ACTION IN PROSTATE CANCER

WETHERILL, YELENA B

Abstract Details

2005, PhD, University of Cincinnati, Medicine : Cell and Molecular Biology.
Androgens are critical for prostate development, growth and survival. As such, treatment for advanced prostatic adenocarcinomas is reliant on the initial androgen dependence of this tumor type. The goal of these therapies is to block androgen receptor (AR) action either through direct inhibition of the receptor or through inhibition of androgen synthesis. Although hormonal therapy is initially effective in most patients, recurrent tumors ultimately arise and lead to patient morbidity. It is increasingly evident that AR plays a critical role in progression of prostate cancer (CaP) to hormone-refractory state, as such recurrent tumors harbor restored AR activity. One mechanism of such re-activation occurs through AR mutations, rendering the receptor responsive to non-canonical ligands. We show that nanomolar concentrations of bisphenol A (BPA), a known estrogenic industrial compound, initiate androgen-independent proliferation in LNCaP human prostatic adenocarcinoma cells by activating a tumor-derived AR allele (T877A). We also demonstrate that full mitogenic action of BPA in LNCaP cells is dependent upon activation of the tumor-derived AR-T877A. Based on these data, we propose that BPA activates specific nuclear receptors in advanced prostate cancers, thus inducing inappropriate CaP cell proliferation. Moreover, BPA exposure may facilitate the development of hormone-refractory prostate tumors. Supporting the first part of our hypothesis, we illustrate that BPA transactivates multiple tumor-derived AR alleles in the absence of testicular androgens, thus expanding the potential influence of xenoestrogens on prostate cancer. Furthermore, we show that BPA cooperates with androgen in activation of mutant AR alleles. In vitro radioligand binding assays revealed that BPA alters 5a-dihydrotestosterone binding to AR-T877A, likely through non-competitive inhibition, and at high concentrations it blocks proliferation of AR positive, androgen-dependent prostate adenocarcinoma cells (LNCaP, LAPC-4). Finally, we demonstrate that in vivo exposure of LNCaP prostate tumors to environmentally relevant BPA concentrations results in accelerated tumor growth and therapy bypass as illustrated by increased serum levels of prostate specific antigen (PSA) relative to the placebo-treated animals. Together, these data demonstrate that BPA can serve as a potential “hormone sensitizer” of the mutant androgen receptors present in advanced prostate adenocarcinomas, thereby possibly contributing towards therapeutic relapse in advanced prostate cancer patients and supporting the notion that non-steroidal environmental compounds can alter the function of nuclear receptor complexes.
Dr. Karen Knudsen (Advisor)
146 p.

Recommended Citations

Citations

  • WETHERILL, Y. B. (2005). PLEIOTROPIC EFFECTS OF XENOESTROGEN ACTION IN PROSTATE CANCER [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1109257593

    APA Style (7th edition)

  • WETHERILL, YELENA. PLEIOTROPIC EFFECTS OF XENOESTROGEN ACTION IN PROSTATE CANCER. 2005. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1109257593.

    MLA Style (8th edition)

  • WETHERILL, YELENA. "PLEIOTROPIC EFFECTS OF XENOESTROGEN ACTION IN PROSTATE CANCER." Doctoral dissertation, University of Cincinnati, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1109257593

    Chicago Manual of Style (17th edition)