Unique bisphenol a transcriptome in prostate cancer: novel effects on ER[beta] expression that correspond to androgen receptor mutation status

Environmental Health Perspectives, Nov, 2007 by Janet K. Hess-Wilson, Siobhan L. Webb, Hannah K. Daly, Yuet-Kin Leung, Joanne Boldison, Clay E.S. Comstock, Maureen A. Sartor, Shuk-Mei Ho, Karen E. Knudsen

Discussion

Somatic mutation of the AR is known to drive recurrent tumor formation in a significant percentage of patients undergoing hormone therapy (Feldman and Feldman 2001; Hirawat et al. 2003; Marcelli et al. 2000; Navarro et al. 2002; Taplin et al. 2003; Veldscholte et al. 1992a), and it has been shown previously that selected AR mutants become receptive to activation by the environmental contaminant BPA. The clinical ramifications of BPA activating tumor-derived mutant ARs and inducing androgen-independent tumor cell proliferation may be substantial, as BPA can reduce therapeutic efficacy in xenograft models (Wetherill et al. 2006). While these data point toward the potential for BPA to assist tumor cells in escaping therapy, the molecular mechanisms of this process were not well understood. In this study, the molecular consequence of BPA action was identified under conditions in which BPA promotes androgen-independent proliferation. Gene expression analyses revealed that in AR-T877A-expressing cells, BPA elicited an overlapping but distinct molecular signature compared with that induced by exposure to canonical AR ligand (DHT). Unexpectedly, detailed examination of the most significant targets demonstrated that BPA exposure elicited dramatic reduction in expression of ER , a nuclear receptor that is proposed to antagonize AR activity and androgen-dependent proliferation in prostatic epithelia (Leav et al. 2001; Pravettoni et al. 2007; Weihua et al. 2001). Comparative analyses revealed that while DHT exposure also reduced ER[beta], this effect was marginal compared with the BPA response. Last, the ability of BPA (but not DHT) to attenuate ER[beta] function appears to be specific to cell type and putatively receptor specific, as BPA had no detectable effect on ER[beta] expression in cells containing wild-type AR or AR-H874Y. Notably, these also represent cell types in which BPA fails to induce cellular proliferation. Together, these data indicate that the ability of BPA to induce androgen-independent cellular proliferation is associated with AR-T877A expression and a unique gene expression signature that involves down-regulation of ER[beta].

Combined with these observations, the concept that BPA induces cell-specific transcriptional profiles is emerging. For example, transcriptional analysis of BPA exposure on breast cancer cells (MCF-7) revealed that BPA up-regulated a significant number of genes involved in cell cycle progression and purine and pyrimidine metabolism (Shioda et al. 2006), reaffirming the proliferative biological action of this compound in estrogendependent tissues. Interestingly, it has been shown that BPA exposure increases ER[beta] in some breast cancer lines (Cappelletti et al. 2003), suggesting that the direct activation of ERs by BPA may facilitate the proliferative response to these tissues. Additionally, it has been shown that higher levels of BPA uniquely regulate growth-and developmentrelated genes in breast cancer cells (Singleton et al. 2006). From these data it is clear that in estrogen-sensitive mammary tissues, BPA exposure modulates pathways with important biological outcomes (e.g., cell cycle progression), and that the effects of BPA augment the known proliferative response to ER activation in this tissue type.