Abstract LT10: Molecular mechanisms of SOCS1-mediated tumor suppression in prostate cancer

Abstract Prostate cancer is the most commonly diagnosed cancer among men and is a leading cause of cancer mortality. Prostate cancer risk is increased by prostatitis and benign prostate hyperplasia (BPH). Urogenital infections that cause prostatic inflammation are an important risk factor for BPH and PCa, however the underlying molecular mechanisms are not yet well understood. Suppressor of cytokine signaling 1 (SOCS1) is an important regulator of inflammatory cytokines and an inhibitor of cytokine and growth factor signaling. SOCS1 is a tumor suppressor protein implicated in p53 activation. Low protein expression of SOCS1 in human PCa specimens is associated with increased disease severity. To understand the mechanisms of SOCS1-mediated tumor suppression in the prostate gland, we ablated the Socs1 gene in prostate epithelial cells. These prostate epithelial cell-specific Socs1 knockout (Socs1 ΔPE ) mice show normal prostate development and maturation. However, after attaining puberty, Socs1 ΔPE mice develop progressive prostate hyperplasia of luminal epithelial cells and inflammatory cell infiltration. Upon infection with a clinical isolate of colibactin positive uropathogenic E. coli (UPEC), Socs1 ΔPE mice develop invasive prostate cancer with complete loss of lobular architecture. Prostate epithelial cell organoids from Socs1 ΔPE mice display multilayered luminal epithelium with increased cell proliferation. Monolayers of organoid-derived epithelial cells from Socs1 ΔPE mice show increased sensitivity to DNA damage following exposure to UPEC. These findings suggest that SOCS1 expression maintains homeostasis of the prostate gland by attenuating inflammation and exerts tumor suppression by conferring protection against DNA damage. The Socs1 ΔPE mouse model will be a useful to elucidate pathogenic mechanisms of inflammation-driven prostate cancer development and to test anti-inflammatory treatment regimens to halt disease progression. Citation Format: Awais Ullah Ihsan, Mozhdeh Namvarpour, Anny Armas Cayarga, Alfredo Menendez, Sheela Ramanathan, Subburaj Ilangumaran. Molecular mechanisms of SOCS1-mediated tumor suppression in prostate cancer [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr LT10.