THU488 Genetic Alterations In CREBRF Influence Prostate Cancer Survival And Impact Prostate Tissue Homeostasis In Mice

Abstract

Abstract Disclosure: L.E. Pascal: None. K.A. Frahm: None. K. Skalitzky: None. D.B. DeFranco: None. L. Rigatti: None. R. Lu: None. T. Liu: None. Background: Risk factors for prostate cancer include age, environmental factors, race and ethnicity. Genetic variants in cyclic-adenosine-monophosphate-response-element-binding protein 3 regulatory factor (CREBRF) gene are frequently observed in Pacific Islanders, a population with elevated prostate cancer incidence. CREBRF has been shown to play a role in other cancers, however its function in prostate homeostasis and tumorigenesis has not been previously explored. Methods: Alterations in CREBRF were identified in prostate cancer patients via in silico analysis of several publicly available datasets through cBioPortal. Male Crebrf knockout mice were generated and examined for prostate defects at 4 months of age. Immunohistochemical staining of murine prostate sections was used to determine the impact of Crebrf knockout on proliferation, apoptosis, inflammation and blood vessel density in the prostate. Serum adipokine levels were measured using a Luminex Multiplex Assay. Results: CREBRF alterations were identified in up to 4.05% of prostate tumors and the mutations identified were categorized as likely damaging. Median survival of patients with CREBRF alterations was 41 months, compared to 131 months for patients without CREBRF alterations. In the murine model, the prostates of Crebrf knockout mice had reduced epithelial proliferation and increased TUNEL+ apoptotic cells. Circulating adipokines PAI-1 and MCP-1 were also altered in Crebrf knockout mice compared to age-matched controls. Conclusions: Prostate cancer patients with CREBRF alterations were associated with decreased overall survival suggesting that CREBRF may play a role in prostate tumorigenesis and progression. The murine knockout model demonstrated that CREBRF could modulate proliferation and apoptosis and macrophage density in the prostate. Serum levels of adipokines PAI-1 and MCP-1 were also altered and could contribute to the phenotypic changes observed in the prostates of Crebrf knockout mice. Future studies focused on populations susceptible to CREBRF mutations and mechanistic studies will be required to fully elucidate the potential role of CREBRF in prostate tumorigenesis. Presentation: Thursday, June 15, 2023