Abstract B11: Re-wired E2F function in response to RB loss as a potential driver of castration-resistant prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the most frequently diagnosed non-cutaneous malignancy, and second leading cause of cancer death in males in the United States, causing over 30,000 deaths per year. A crucial component to the development and progression of PCa is the activity of the androgen receptor (AR). AR promotes proliferation and is required for PCa cell growth and survival. As such, targeting the AR-signaling axis through androgen deprivation therapy (ADT) is the first line of therapy for PCa. However, cells invariably become resistant to this therapy and men relapse with the incurable form of the disease, castration-resistant prostate cancer (CRPC). It has been shown that an underlying mechanism of this resistance revolves around the retinoblastoma (RB) tumor suppressor protein. RB functions to repress tumor development by negatively regulating the activity of the E2F family of transcription factors thus, resulting in a decrease in AR levels. RB additionally controls cell cycle progression through its ability to bind and inhibit E2F1 mediated transcription of genes required for G1/S progression. Surprisingly, genome-wide assessment of E2F activity in the absence of RB has been understudied. To better understand the molecular pathways that are altered upon RB loss and the roles they play in CRPC, RNA-Seq and ChIP-Seq analyses were performed in isogenic RB cell lines in both hormone sensitive and CRPC models. Data to be discussed reveal new insight into the differential effects of RB loss on AR and E2F1 function and role as potential drivers of late stage disease. Citation Format: Amy C. Mandigo, Chris McNair, Matthew J. Schiewer, Kexin Xu, Fugen Li, Brown Myles, Karen E. Knudsen. Re-wired E2F function in response to RB loss as a potential driver of castration-resistant prostate cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B11.