BAF57 Deregulation Orchestrates Novel Oncogenic Signaling and Prostate Cancer Progression

Prostate cancer (PCa) is one of the leading causes of male mortality in the developed world. The development and progression of PCa is heavily reliant on signaling by the androgen receptor (AR), a ligand-dependent transcription factor. Therefore, AR is the target of current therapies for non-organ confined disease. However, patients relapse approximately 2-3 years after initial treatments using AR antagonists, resulting in recalcitrant disease. This advanced stage of cancer, often termed castration resistant prostate cancer (CRPC), has no effective cure. Therefore, the need for novel, efficacious intervention warrants meticulous investigation of components impinging on AR signaling. The studies described herein define the role of the BAF57 subunit of the SWI/SNF family of chromatin remodeling factors in modulating AR activity with consequences for PCa progression. The first study furnished evidence for the physical interaction of BAF57 with AR and the BAF57 requirement for early AR transcriptional response to ligand. This interaction constituted the basis for the development of a novel peptide inhibitor, termed the BAF57-Inhibitory Peptide (BIPep), to disrupt androgen-dependent, AR-mediated PCa cell proliferation. Targeting the AR-BAF57 interaction could serve as a novel therapeutic approach to block AR activity, since this strategy is directed towards a critical region of AR that is not currently targeted in disease. Moreover, BAF57 upregulation was observed in a small cohort of human PCa specimens. These findings prompted a second study examining the consequences of tumor-derived BAF57 upregulation in clinical samples of high-grade primary and metastatic PCa. Modeling the tumor-derived BAF57 elevation in vitro, followed by microarray analyses, demonstrated the unique upregulation of cytoskeletal remodeler genes such as integrins, with concomitant SWI/SNF anomalies. Integrins are involved in directing pro-migratory, pre-metastatic processes. This study is one of the few to highlight the utility of BAF57 signaling as a potential biomarker of aggressive metastatic disease outcomes. Elucidation of BAF57-governed novel signaling could pave the way for understanding the molecular mechanisms underpinning metastatic PCa and aid the design of putative therapeutic strategies for currently incurable advanced PCa

Caveolin-1 overexpression enhances androgen-dependent growth and proliferation in the mouse prostate

Prostate cancer (PCa) continues to be one of the leading causes of cancer-related deaths among American men. The prostate relies upon the androgen receptor (AR) to mediate the effects of androgens on normal growth, a reliance that is maintained during malignant prostate growth. Caveolin-1 (Cav-1), the main structural component of caveolae, has been shown to promote the malignant growth and invasion of prostate tumors. In vitro work has shown that Cav-1 can act as an AR coactivator by enhancing its transciptional activity. However, it is unknown how Cav-1 affects androgen-dependent growth and signaling in vivo. To explore this role, a novel mouse model of Cav-1 overexpression was developed with a hormone-insensitive promoter. Cav-1 transgenic (Tg) mice subjected to castration and androgen stimulation display enlarged prostate weights and increased DNA synthesis. Through gene transcript and proteomic profiling, we demonstrate that Cav-1 overexpression favors androgen-regulated responses and enhances processes involved in transcription, cell cycle progression and protein synthesis. Interestingly, Cav-1 overexpression was associated with an increase in the phosphorylation of AR on serine 210, a post-translational modification linked to its activity under androgen-stimulated conditions. In addition, these mice exhibited an increase in the phosphorylation of ribosomal S6 protein on serine 235/236 (pS6), a marker of protein synthesis and a downstream component of the mTOR pathway. Thus, Cav-1 Tg mice could serve as a novel model for studying AR-regulated pathways involved in prostate growth and proliferation. © 2011 Elsevier Ltd. All rights reserved