Abstract LB-085: RB loss-induced genome wide E2F1 reprogramming drive advanced prostate cancer
Authors: McNair Christopher , Xu Kexin , Mandigo Amy , Benelli Matteo , Leiby Benjamin , Rodrigues Daniel , Lindberg Johan , Gronberg Henrik , Visakorpi Tapio , Li Fugen , Bono Johann De , Demichelis Francesca , Rubin Mark , Brown Myles , Knudsen Karen E. 
Published: July 2017

Prostate adenocarcinoma (PCa) is the most highly diagnosed non-cutaneous malignancy in the United States and the third most lethal among men in this category. First line therapies targeting disruption of the androgen receptor (AR) signaling axis are initially effective, however within 2-3 years patients commonly relapse, due in part to reactivation of the receptor, and progress to the ultimately fatal form of the disease (castrate resistant prostate cancer, CRPC). Interestingly, recent examination of CRPC identified a major mechanism of progression as loss of the retinoblastoma (RB) protein. Along with its critical role in controlling cell cycle progression, RB is known to have important tumor suppressor functions, and has been shown in PCa to be lost exclusively in late stage disease. Additionally, loss of RB has been shown to correlate with increases in both AR and E2F1 expression, via E2F dependent mechanisms. Despite the vital role RB loss has been shown to play in this fatal stage of disease, the molecular underpinnings remain undefined. Thus, in order to elucidate these CRPC specific alterations, the current study utilizes isogenic models of RB loss in combination with genome wide binding and transcriptional studies. Data presented herein demonstrate that loss of RB is frequent in CRPC, however this phenomenon is not correlated with changes in proliferative indices, suggested a role for RB loss outside of cell cycle control. Further, RB loss induces genome wide transcriptional changes in PCa cells in castrate conditions, including up-regulation in Myc, E2F, and DNA-repair related pathways. Additionally, RB loss significantly expands E2F1 binding capacity, while maintaining the majority of the RB-intact E2F1 cistrome. Strikingly, while the current RB/E2F1 paradigm suggests that E2F1 exclusively occupies promoter regions of DNA in order to regulate transcriptional changes, RB loss induces sweeping reprogramming of E2F1 occupied regions, with a marked increase in enhancer-bound E2F1. Further, motif analyses suggest divergence away from canonical E2F1 binding motifs after RB loss specifically in regions of expanded E2F1 binding, and additionally suggest likely interaction of novel E2F1 co-factors under RB loss conditions. Finally, interrogation of a CRPC patient tumor cohort showed predictive capacity for RB-loss induced E2F1 binding and differentially expressed gene signature to select for RB loss in patient samples, indicating a novel E2F1 driven set of targets vital for CRPC transition in human disease. Together, these data present the first insight into E2F1 activity resulting from RB loss, and the role these changes play in progression to CRPC.

Citation Format: Christopher McNair, Kexin Xu, Amy Mandigo, Matteo Benelli, Benjamin Leiby, Daniel Rodrigues, Johan Lindberg, Henrik Gronberg, Tapio Visakorpi, Fugen Li, Johann De Bono, Francesca Demichelis, Mark Rubin, Myles Brown, Karen E. Knudsen. RB loss-induced genome wide E2F1 reprogramming drive advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-085. doi:10.1158/1538-7445.AM2017-LB-085