Androgen receptor molecular biology and potential targets in prostate cancer

Abstract

The androgen receptor (AR) is a key transcriptional regulator and therapeutic target in prostate cancer. During androgen deprivation therapy to treat metastatic prostate cancer, surviving cells acquire increased AR signaling through a variety of mechanisms, one of which is enhanced interactions with AR coactivators. One recently identified AR-specific coregulator expressed only in human and nonhuman primates is the melanoma antigen gene protein-A11 (MAGE-11). MAGE-11 increases AR transcriptional activity through direct interactions with AR and other coactivators, and its levels increase during prostate cancer progression to castration-recurrent growth. The MAGE-11 gene is located at Xq28 on the human X chromosome as part of an X-linked MAGE gene family of cancertestis antigens. MAGE-11 stabilizes AR when androgen levels are low, and functions in a transcriptional hub to promote AR-mediated gene activation. The evolutionary development and organization of the MAGE-11 gene within the cancertestis antigen family suggests that MAGE-11 provides a gain-of-function to AR among primates in both normal physiology and cancer, and may serve as a therapeutic target in the treatment of advanced prostate cancer.

Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor

“…The evolution of the MAGE-A11 among primates, its increased expression during androgen deprivation therapy of prostate cancer, its function as an AR coregulator, and the requirement for MAGE-A11 in prostate cancer cell growth support the concept that MAGE-A11 is a proto-oncogene that hyperactivates human AR and promotes the development of castration-resistant prostate cancer (38). One mechanism for the increase in MAGE-A11 in prostate cancer clinical samples during androgen deprivation therapy and in the CWR22 human xenograft model of prostate cancer that undergoes remission after castration but regrows after castration is progressive hypomethylation of CpG dinucleotides at the transcription start site of the MAGE-A11 gene promoter (2,3). MAGE-A11 expression is also up-regulated in prostate cancer during androgen deprivation therapy by increasing levels of cAMP associated with down-regulation of phosphodiesterases that degrade cAMP (2, 60 -63).…”

“…MAGE-A11 is a cancer-testis antigen that resides predominantly in the nucleus at low levels in normal human reproductive tract tissues and at higher levels in castration-resistant prostate cancer (1)(2)(3)(4)(5)(6). Although named initially for its identification in melanoma (7,8), MAGE-A11 is a coregulator of human AR and progesterone receptor-B (1,6,9).…”

X chromosome gain in male breast cancer

“…Both AR and its regulator MAGE-11 are mapped on chromosome X, respectively on Xq12 and Xq28, therefore a possible role in recurrence and resistance to anti-androgen therapy has been advocated [14] .…”

Melanoma Antigen-A11 (MAGE-A11) Enhances Transcriptional Activity by Linking Androgen Receptor Dimers

“…MAGE-A11 stabilizes AR at low androgen levels, which may account for the increase in AR protein in castration-recurrent prostate cancer (9 -11). MAGE-A11 functions as an important coregulator that increases AR transcriptional activity during prostate cancer progression (12).…”