Dysregulation of individual SWI/SNF subunits plays tissue and subunit-specific roles in tumorigenesis, disease progression, and therapeutic resistance. This application will assess the role of the BAF57 SWI/SNF subunit in the context of prostate development and prostate cancer (PCa). In PCa, fatal disease arises as a failure to control androgen receptor (AR) activity, and BAF57 is a known effector of AR. Notably, first line therapy for disseminated PCa relies on AR-directed therapeutics. While initially effective, recurrent, incurable tumors form within 2-3 years. Substantive evidence shows that the incurable, "castration-resistant" stage (referred to as castration-resistant prostate cancer, CRPC) is driven by resurgent AR activity. Major lines of investigation support the hypothesis that BAF57 deregulation induces alterations in SWI/SNF that support aberrant AR activity and progression to CRPC. This application will challenge the in vivo impact of BAF57 in prostate development and disease: First, we showed that BAF57 binds directly to AR, is recruited to in the presence of androgen to sites of AR function, and promotes androgen- dependent gene expression in a SWI/SNF-reliant manner. These BAF57 functions proved critical, as ablation of BAF57-AR interaction nullified ligand-dependent AR activity. Parallel studies showed that even modest changes in SWI/SNF subunit expression can have potent effects on SWI/SNF function, molecular output, and cellular phenotypes. Thus, our data underscore the importance of delineating the precise role of BAF57 in SWI/SNF and AR signaling. Strikingly, there is no understanding as to means by which BAF57 influences SWI/SNF activity (in any tissue) under conditions of tumorigenesis or homeostasis. Here, we will use novel genetic models of BAF57 depletion to delineate the molecular impact of BAF57 on SWI/SNF assembly, androgen-dependent AR cistromes, and prostate development (Aim 1). Second, our data indicate that BAF57 is significantly deregulated in high-grade PCa and CRPC. New models mimicking this event revealed a role for BAF57 in promoting for castration-resistant AR signaling. As AR binds to and modulates differential targets in CRPC, it is essential to assess the impact of tumor-associated BAF57 deregulation on the AR cistrome, the consequence for transcriptional regulation, and the clinical relevance of these observations (Aim 2). Third, tumor-associated BAF57 deregulation was predominant in lymph node deposits of CPRC, and deregulation of BAF57 in cells derived from lymph node metastases rendered cells resistant to androgen ablation in vitro. Thus, it is critical to challenge the in vivo consequence of tumor- associated BAF57 deregulation on tumor aggressiveness, lymph node metastasis, and therapy-resistance (Aim 3). Together, these novel aims will illuminate the means by which BAF57 influences SWI/SNF signaling and AR function, assess the in vivo consequence of both events, and define the consequence of tumor-associated BAF57 deregulation on disease progression.
There is a significant need to understand the mechanisms that lead to prostate cancer development and that promote lethal, castration-resistant tumor growth. Our data show that dysregulation of BAF57, a subunit of selected SWI/SNF chromatin remodeling complexes, promotes phenotypes associated with lethal disease. The studies here will challenge this concept using novel in vivo models, will provide molecular insight into the cellular and clinical consequence of BAF57 dysregulation, and have the potential for rapidly translatable outcomes to improve prostate cancer management.
|Schrecengost, Randy S; Dean, Jeffry L; Goodwin, Jonathan F et al. (2014) USP22 regulates oncogenic signaling pathways to drive lethal cancer progression. Cancer Res 74:272-86|
|Schiewer, Matthew J; Knudsen, Karen E (2014) Transcriptional roles of PARP1 in cancer. Mol Cancer Res 12:1069-80|
|Goodwin, Jonathan F; Knudsen, Karen E (2014) Beyond DNA repair: DNA-PK function in cancer. Cancer Discov 4:1126-39|
|Knudsen, Karen E (2014) Hormone whodunit: clues for solving the case of intratumor androgen production. Clin Cancer Res 20:5343-5|
|Goodwin, Jonathan F; Schiewer, Matthew J; Dean, Jeffry L et al. (2013) A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov 3:1254-71|
|Comstock, Clay E S; Knudsen, Karen E (2013) IGF2 revs the steroidogenesis engine. Endocr Relat Cancer 20:C19-21|