Unfaithfulness and promiscuity of a mutant androgen receptor in a hormone-refractory prostate cancer

Abstract

Missense mutations in the androgen receptor (AR) contribute to the failure of hormonal therapy for prostate cancer (PCa), but the underlying molecular bases remain uncharacterized. Here, we describe a new AR variant found in a hormone-refractory metastatic PCa, in which threonine 575 in the DNA binding domain, and threonine 877 in the ligand-binding domain, were both replaced by an alanine. Using gene reporter assays, we demonstrate that the T575A mutation weakened transcriptional activity from promoters containing AR-specific responsive elements, while activity from promoters with AR-non-specific elements was enhanced. Data from gel shift experiments revealed a preferential binding of the T575A mutant to AR-non-specific motifs. We demonstrate that the two mutations T575A and T877A cooperate to confer new functional properties on the AR, and that the mutant AR functions simultaneously as a promiscuous AR due to the T877A mutation, and an unfaithful AR due to the T575A mutation.

Steroidogenic Factor 1 Promotes Aggressive Growth of Castration-Resistant Prostate Cancer Cells by Stimulating Steroid Synthesis and Cell Proliferation

“…This finding is consistent with epidemiologic reports of the human disease; whereas it has long been recognized that androgens have permissive roles in prostate cancer, they are insufficient to induce it on their own (74). Furthermore, promiscuity of the AR has been implicated in reactivation of the receptor (75,76). Meanwhile, the role of local estrogens has been established in promoting abnormal cell proliferation in the prostate, especially when present in combination with androgens (77).…”

Molecular biology of androgen-independent prostate cancer: the role of the androgen receptor pathway

“…5AR, 5-alpha reductase; TKI, tyrosine kinases; mut AR, mutated AR; Amp AR, amplified AR; HDACI, histone deacetylases inhibitors change of the effect of the anti-androgen, which acquires an agonist function and stimulates AR. This agonist function of the anti-androgen may explain the response to antiandrogen withdrawal that can be observed in up to 30% of patients [13][14][15][16][17][18][19][20]. Currently, new anti-androgens are in clinical development: MDV-3100 binds AR in cells with 10-fold higher affinity than bicalutamide, completely inhibits growth of castration-resistant, impairs AR nuclear translocation and blocks DNA binding.…”

Discovery and Mechanistic Characterization of a Novel Selective Nuclear Androgen Receptor Exporter for the Treatment of Prostate Cancer

“…All currently available AR antagonists competitively bind AR and recruit corepressors such as NCoR and SMRT to repress transcription of target genes (10). However, altered intracellular signaling, AR mutations, and increased expression of coactivators lead to functional impairment of antagonists or even transformation of antagonists into agonists (10,11). Studies have shown that mutation of W741 and T877 within AR converts bicalutamide and hydroxyflutamide, respectively, to agonists (12,13).…”