Androgen receptor and its splice variants in prostate cancer
Androgen receptor (AR) is a transcription factor that becomes active upon binding to androgens via its ligand-binding domain (LBD) or in response to signaling cascades initiated by growth factors and cytokines. The activity of AR requires regions within the N-terminal domain (NTD) in a manner that is distinct from the activation of related steroid hormone receptors. Unequivocal evidence has been amassed to consider that the AR axis is the most critical pathway for the progression of prostate cancer. Qualitatively distinct insights into AR pathobiology have been garnered including that AR-regulated gene expression is stage-specifically modulated during disease progression and that the ligand requirement for AR activity could be rendered dispensable because of the expression of constitutively active AR splice variants that are devoid of LBD. The recent appreciation of the clinical challenge that stems from non-gonadal androgens that are not inhibited by traditional hormonal therapies has been tangibly translated into the development of more potent drugs that can potentially lead towards achieving an androgen-free environment. The pre-clinical evidence that proves that AR NTD is a druggable target also forecasts a further paradigm shift in the management of advanced prostate cancer. These advancements together with the identification of more robust AR antagonists and their promising clinical outcome have renewed the hope that targeting the AR pathway remains a sound strategy in the clinical management of prostate cancer. Here, we address these developments with a greater emphasis on the rapidly growing literature on AR splice variants.
KeywordsAndrogen receptor Splice variants Castration-resistant prostate cancer CRPC NTD Amino-terminus LBD Prostate cancer
This work was supported by grants from the Canadian Institutes of Health Research (MOP-84325) and the US National Cancer Institute (2R01 CA105304).
- 2.Hu R, Isaacs WB, Luo J (2011) A snapshot of the expression signature of androgen receptor splicing variants and their distinctive transcriptional activities. The Prostate. doi: 10.1002/pros.21382
- 8.Labrie F, Cusan L, Gomez JL, Martel C, Berube R, Belanger P, Belanger A, Vandenput L, Mellstrom D, Ohlsson C (2009) Comparable amounts of sex steroids are made outside the gonads in men and women: strong lesson for hormone therapy of prostate and breast cancer. J Steroid Biochem Mol Biol 113(1–2):52–56PubMedCrossRefGoogle Scholar
- 21.Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A, Kim K, Sawyers CL (2010) Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci USA 107(39):16759–16765PubMedCrossRefGoogle Scholar
- 35.Mani RS, Tomlins SA, Callahan K, Ghosh A, Nyati MK, Varambally S, Palanisamy N, Chinnaiyan AM (2009) Induced chromosomal proximity and gene fusions in prostate cancer. Science 326(5957):1230Google Scholar
- 36.Steinkamp MP, O’Mahony OA, Brogley M, Rehman H, Lapensee EW, Dhanasekaran S, Hofer MD, Kuefer R, Chinnaiyan A, Rubin MA et al (2009) Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res 69(10):4434–4442PubMedCrossRefGoogle Scholar
- 46.Sadar MD, Williams DE, Mawji NR, Patrick BO, Wikanta T, Chasanah E, Irianto HE, Soest RV, Andersen RJ (2008) Sintokamides A to E, chlorinated peptides from the sponge Dysidea sp. that inhibit transactivation of the N-terminus of the androgen receptor in prostate cancer cells. Org Lett 10(21):4947–4950PubMedCrossRefGoogle Scholar