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GRB10 as a key regulator contributing to the development of castration-resistant prostate cancer Hao, Jun

Abstract

Prostate cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths in North American men. Androgen-deprivation therapy (ADT) is the standard treatment for patients with either locally-advanced or metastatic prostate cancer (PCa). While most PCa patients initially respond to androgen ablation, progression to recurrent castration-resistant prostate cancer (CRPC) commonly occur. Current therapies for CRPC, e.g. next-generation ADT including Enzalutamide and Abiraterone, can extend patients’ lives but are not curative as resistance to their use eventually emerges. As such, there is an urgent need to identify hitherto unrecognized but critical molecular mechanisms driving CRPC, which may in turn lead to novel treatments that can be used in combination with ADT for more effective therapy. In this doctoral dissertation, we examined the transcriptome profiling data of hormone-naïve prostate cancer (HNPC) patient-derived xenografts (PDXs) for gene expression changes at various time points after castration. Particular attention was given to expression changes that appeared early during CRPC development, indicative of genes acting as potential CRPC drivers. Eighty genes were found to be significantly upregulated at the CRPC stage, while 7 of them also showed elevated expression before CRPC development. Among the latter, Growth Factor Receptor Bound Protein 10 (GRB10), was the most significantly and consistently upregulated gene. Moreover, we found that GRB10 expression was elevated in clinical CRPC compared to HNPC in several clinical cohorts. Functionally, we found that GRB10 knockdown markedly reduced prostate cancer cell proliferation and AKT activity. Further investigation suggests that GRB10 is transcriptionally regulated by androgen receptor through an androgen responsive element located in GRB10’s intron. Mechanistically, through unbiased immunoprecipitation-mass spectrometry (IP-MS), we demonstrated that GRB10 could directly bind to and reduce the expression of protein phosphatase 2A (PP2A), a well-established tumor suppressor. These data suggest that GRB10 plays an important role in CRPC development and progression. This research demonstrates the functional roles of GRB10 in CRPC development and defines its molecular mechanisms driving ADT resistance. This study improves our understanding of the mechanisms underlying prostate cancer progression, paving the road for developing therapeutic agents that would improve the efficacy of current CRPC treatments.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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