Abstract
Abstract Androgen ablation therapy is the standard treatment for advanced prostate cancer. While tumors initially respond to androgen deprivation, they almost always recur with an androgen-independent phenotype termed castration-resistant prostate cancer (CRPC). Castration-resistant tumors are incurable with current therapy regimens and account for most prostate cancer mortality. Better understanding of their biology is therefore critical for devising novel treatment options. Steroid Receptor Coactivator 3 (SRC-3) is a nuclear receptor coactivator that promotes growth of endocrine tissues. It enhances proliferation of prostate cancer cell lines and is highly expressed in advanced human prostate tumors. Despite this, the role of SRC-3 in CRPC is not well studied. PTEN is a tumor suppressor gene mutated in most human prostate cancers. Mice harboring PTEN deletion in prostatic epithelial cells develop cancer that arises from progenitors in the luminal epithelial and basal compartments. Tumors histologically mimic advanced human disease and are castration-resistant. We hypothesized that, in prostate tumors caused by PTEN deletion, SRC-3 is a critical mediator for accelerating the development of CRPC. To test this hypothesis, we generated mice in which floxed PTEN and SRC-3 genes were concomitantly deleted in prostate epithelial cells via a Cre recombinase driven by the Probasin promoter. We first compared tumor mass, histology and biomarkers in these PTENf/f/SRC-3f/f/ARR2PBiCre (pten3cko) mice vs. PTENf/f/ARR2PBiCre (ptencko) mice. We found that while tumor growth in pten3cko mice was slightly inhibited at 9 wks of age, tumor histology and cellular composition were not markedly different. We then castrated mice of both genotypes at 9-wks-old and harvested tumors at 12wks. Interestingly, castrated ptencko mice had significantly worsened tumor aggressiveness–as indicated by increased proliferation index, reduced differentiation (increased p63; decreased K5 and K8) and increased reactive stroma (double staining of SMA and vimentin)–versus their non-castrated counterparts. Amazingly, in addition to significantly reducing tumor size, SRC-3 ablation reversed all changes comprising the aggressive phenotype seen in the post-castration tumors. Further investigation showed SRC-3 deletion decreased mTOR signaling. Together, these data show that castration induces a worse tumor phenotype in the setting of PTEN deletion and that SRC-3 promotes this process by inducing epithelial cell proliferation and enhancing the growth-promoting effect of these cells on the stroma. Therefore, SRC-3 may serve as a potential target for controlling CRPC development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3296. doi:1538-7445.AM2012-3296
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