Background: Although most patients with advanced prostate cancer are initially successfully treated with androgen ablation, the disease eventually becomes hormone-refractory accompanying poor prognosis. One mechanism of relapse occurs through the mutation of androgen receptor (AR) rendering the receptor responsive to non-specific ligands such as estrogens. It has recently been reported that the estrogen-sensitive M749L AR mutant is regulated by both dihydrotestosterone (DHT) and 17β-estradiol (E2), and T877A AR mutant is regulated by bisphenol A (BPA), an environmental estrogen. We now report the effect of phytoestrogens and environmental estrogen on the transcriptional activity of AR mutants.
Methods: COS7 cells were transfected with an androgen responsive element/reporter gene and AR expression plasmid (wild type, M749L, T877A or W741C). After transfection, they were treated with DHT, E2, genistein, daidzein, coumestrol, BPA, p-n-nonylphenol (NP), or bis(2-ethylhexyl)phthalate (DEHP). Genistein, daidzein and coumestrol are phytoestrogens and BPA, NP and DEHP are environmental estrogens. The transcriptional activity of AR was measured by a luciferase assay method.
Result: All estrogenous chemical slightly activated T877A mutant in the absence of DHT or E2, but they did not activate other AR mutants or wild type AR with the exception of daidzein that activated wild type AR. All environmental estrogens inhibited the transcriptional activity of wild type and mutant AR in the presence of DHT. Furthermore BPA and NP, but not DEHP, inhibited the activity of M749L mutant in the presence of E2. Among the phytoestrogens, genistein and daidzein enhanced the activity of wild type AR but not AR mutants in the presence of DHT. Coumestrol inhibited the activity of T877A mutant but not wild type AR in the presence of DHT. None of the phytoestrogens altered the activity of M749L in the presence of either DHT or E2. Used as controls, flutamide inhibited M749L mutant in the presence of DHT or E2. Tamoxifen inhibited this mutant only in the presence of E2.
Conclusions: Environmental estrogens, such as BPA, NP, and DEHP, have been reported to affect reproductive tissues and increase the incidence of breast cancer in human and animals. The present study suggests that estrogenous chemicals are potential agents for the treatment of prostate cancer that has mutated AR.

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