Date of Award

12-31-2021

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology/Molecular, Cellular, and Organismal Biology

First Advisor

Changmeng Cai

Second Advisor

Jill A. Macoska

Third Advisor

Shailja Pathania

Abstract

Retinoblastoma protein (Rb), encoded by the RB1 gene, functions as a tumor suppressor in cancers by forming a repressor complex with E2F transcription factors to inhibit cell cycle progression. RB1 deficiency mutations or deletions, which cause the hyperactivation of E2F signaling, are found in 5-10% of primary prostate cancer and ~15% of the late-stage castration-resistant prostate cancer (CRPC) and are significantly associated with poor outcomes. Therefore, it is important to understand the global activity and regulation of the Rb-E2F complex in prostate cancer. Recent studies from us have found that androgen receptor frequently co-binds with Rb-E2F and facilitate the recruitment of Rb to strengthen the Rb-E2F repressor complex, leading to the suppression of E2F target genes and G1/S cell cycle progression. This mechanism provides a rationale to treat CRPC with high-dose androgens. In cancer cells, Rb is also hyperphosphorylated by CDK4/6, resulting in its disassociation from E2Fs. While the CDK4/6 inhibitor treatment has been approved for treating multiple cancers, its efficacy in CRPC is not clear. In this project, I aim to determine whether CDK4/6 inhibitor treatment can be combined with high-dose androgen treatment to exploit the repressor activity of Rb-E2F in CRPC.

Comments

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