Abstract 1712: Androgen receptor splicing variants promote therapeutic resistance in prostate cancer

Abstract

Abstract Androgen receptor (AR) plays a key role in progression to incurable castration-resistant prostate cancer. Recently, we and others have identified multiple alternatively spliced AR isoforms in hormone refractory prostate cancer cells. These AR splice variants contain the intact N-terminal transactivation domain and the DNA binding domain, but lack the ligand binding domain. They function as constitutively active transcription factors and their activity is independent of androgen or anti-androgens. Our tissue microarrays analysis on 429 human prostate tissue samples revealed that AR3, one of the major AR splice variants, is significantly up-regulated during prostate cancer progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers castration-resistant growth of prostate cancer cells, whereas specific knockdown of AR3 expression in hormone-resistant prostate cancer cells attenuates their growth under androgen-depleted conditions, suggesting an indispensable role of AR3 in castration-resistant growth of prostate cancer cells. Furthermore, our gene expression microarray analysis showed that AR3 regulates a unique set of target genes which are not regulated by the prototype AR, suggesting that AR3, as an independent transcription factor, utilizes a distinct transcription programs to achieve its distinct and specific biological functions which are important for castration-resistant growth. In addition to its role in the androgen-ablation resistance, the AR isoforms may also be involved in chemotherapeutic resistance. We found that AR3 is overexpressed in chemotherapeutic resistant prostate cancer cell lines that are more tumorigenic, compared with their parental drug-sensitive lines. Therefore, aberrant expression of AR splicing variants may be a general mechanism underlying the development of multiple therapeutic resistances in prostate cancer. Taken together, our data suggest that AR3 may potentially serve as a prognostic marker to predict patient outcome in response to hormonal and chemo therapy, and targeting these AR splicing variants may offer more effective treatment for advanced prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1712.