E2F1 and Androgen Receptor Dysregulation Drives RB-Deficient Cancer Progression
Advanced prostate cancer termed castration-resistant prostate cancer (CRPC) arises from acquired resistance to androgen receptor (AR)-targeted therapies. CRPC remains a uniformly fatal disease, resulting in tens of thousands of deaths each year. One of the mechanisms driving the transition to CRPC is through the loss of the retinoblastoma (RB) tumor suppressor protein. RB is a master regulator of cell cycle progression through the direct control of the E2F family of transcription factors. Specifically, in CPRC, RB loss has been shown to induce a dysregulation of E2F1 leading to increased transcription of AR and subsequent AR activity under androgen deprivation. Interestingly, until now, the impact of RB loss on progression of disease has only been examined in the context of the CRPC transition. The studies herein utilize transcriptomic, cistromic, and metabolomic analyses to reveal that RB loss that occurs as a mechanism of adaptive resistance to AR-targeted therapy is distinct from RB loss that occurs later in disease progression. The studies herein explore the impact of RB loss on E2F1 beyond AR control identifying a significant role for RB loss and E2F1 in reprogramming cancer cell metabolism exclusively in late-stage disease. Gained E2F1 function after RB loss is shown promote an increase in glutathione synthesis, leading to a protection from cytotoxic therapy-induced reactive oxygen species (ROS). Further, RB loss is shown to promote a cooperation between AR and E2F1 in the activation of transcription leading to the identification of an AR/E2F1 cooperome that controls a distinct set of downstream signaling pathways including evasion from apoptosis. RB loss-induced E2F1 control of metabolism and AR and E2F1 cooperation was confirmed in human tumors highlighting the clinical significance of these studies. Overall, RB loss has been identified to have a significant impact on CRPC progression and the studies herein reveal novel mechanisms to target this late-stage, RB-deficient disease.
Mandigo, Amy Catherine, "E2F1 and Androgen Receptor Dysregulation Drives RB-Deficient Cancer Progression" (2021). ETD Collection for Thomas Jefferson University. AAI28652255.