Xenoestrogen Action in Prostate Cancer: Pleiotropic Effects Dependent on Androgen Receptor Status

Abstract

Androgen is critical for prostate development, growth, and survival. Therapies for advanced prostate cancer aim to block androgen receptor (AR) action. However, recurrent tumors ultimately arise, which harbor restored AR activity. One mechanism of such reactivation occurs through AR mutations, rendering the receptor responsive to noncanonical ligands. We have shown previously that a known xenoestrogen, bisphenol A (BPA), activates a tumor-derived AR mutant (T877A), leading to androgen-independent prostate cancer cell proliferation. Here, we show that BPA cooperates with androgen to activate AR-T877A as shown by both reporter assays and increased levels of prostate-specific antigen expression. Further investigations using both yeast and mammalian model systems revealed that multiple AR alleles are responsive to BPA, thus expanding the potential influence of xenoestrogens on prostate cancer. Moreover, in vitro radioligand binding assay revealed that BPA alters 5α-dihydrotestosterone binding to AR-T877A likely through noncompetitive inhibition. We also show that higher concentrations of BPA block proliferation of AR-positive, androgen-dependent prostate adenocarcinoma cells (LNCaP and LAPC-4), with a more modest inhibitory effect on androgen-independent cells (22Rv-1). By contrast, AR-negative prostate cancer cells failed to show growth inhibition after exposure to high BPA dose. Together, these data show that BPA can serve as a potential “hormone sensitizer” of the mutant ARs present in advanced prostate adenocarcinomas, thereby possibly contributing toward therapeutic relapse in advanced prostate cancer patients and supporting the notion that nonsteroidal environmental compounds can alter the function of nuclear receptor complexes.

Endocrine Disruptors Differently Influence Estrogen Receptor β and Androgen Receptor in Male and Female Rat VSMC

“…The principal aim of this work is to evaluate the impact of EDCs on sex‐related differences in VSMC motility by analyzing: (i) the effects and action mechanisms of sex steroid hormones, (ii) the specific effects of EDCs in male and female cells, and (iii) the involvement of ER subtypes and AR activities on the motility of male‐ and female‐derived VSMC. We selected the flavonoid naringenin (Nar) and the plasticizer BPA as EDC prototypes for their well‐known effects and action mechanisms on estrogen receptors (ERs) (Bolli et al, , ; Galluzzo et al, ; ) and androgen receptor (AR) (Wetherill et al, ; Lee et al, ; Kruger et al, ; Xi et al, ).…”

Environmental‐relevant bisphenol A exposure promotes ovarian cancer stemness by regulating microRNA biogenesis

“…39 AR could essentially mediate the actions of BPA in advanced prostate adenocarcinomas. 40 We also provide evidence that a new mechanism in global miRNA regulation is involved in this process, which may well explain the observation of its significant tumour-promoting effects which could provide important insights for setting up guidelines for limiting human exposure.…”

Experimental Exposure to Bisphenol A Has Minimal Effects on Bone Tissue in Growing Rams—A Preliminary Study

“…The endocrine-disrupting activity of BPA has been described through several pathways with an affinity for binding to receptors, such as estrogen (ER) [ 12 , 13 , 14 ], androgen [ 15 ], aryl hydrocarbon receptor [ 16 ], or steroid and xenobiotic receptors [ 17 ]. This binding can disrupt endocrine system function in animals [ 3 , 18 , 19 ].…”