Abstract A51: Disruption of Abi1/Hssh3bp1 expression induces prostatic intraepithelial neoplasia in the conditional Abi1/Hssh3bp1 KO mice

Abstract

Abstract Prostate cancer is one of the leading causes of cancer-related deaths in the United States and a leading diagnosed non-skin cancer in American men. Genetic mutations underlying prostate cancer tumorigenesis include alterations of tumor suppressor genes. We previously proposed that ABI1/hSSH3BP1 acts as a tumor suppressor gene (Macoska, et al. 2001 Neoplasia 3, 99-104). Here, we tested this hypothesis by searching for ABI1 gene mutations in primary prostate tumors from patients, and by analyzing the consequences of prostate-specific disruption of the mouse Abi1/Hssh3bp1 orthologue. We sequenced the ABI1/hSSH3BP1 gene and identified mutations in 15 out of 44 prostate tumors. Moreover, complementation growth-, proliferation- and xenograft- assays using the LNCaP cell line, which contains the loss-of-function Abi1 mutation, and stably expressed wt ABI gene, were consistent with the tumor suppressor hypothesis. To test the hypothesis further, we disrupted the gene in the mouse prostate by breeding the Abi1 floxed strain with the probasin promoter-driven Cre recombinase strain. Histopathological evaluation of mice indicated development of prostatic intraepithelial neoplasia (PIN) in Abi1/Hssh3bp1 KO mouse as early as the 8th month, but no progression beyond PIN was observed in mice as old as 12 months. Observed decreased levels of E-cadherin, β-catenin, and WAVE2 in mouse prostate suggest abnormal cellular adhesion as the mechanism underlying PIN development due to Abi1 disruption. In summary, this study provides further evidence for the hypothesis that Abi1 down-regulation plays a role in the development of prostate cancer and warrants further investigations of Abi1's role in prostate cancer tumorigenesis. Citation Format: Xiaoling Xiong, Leszek Kotula, Anna Chorzalska, Patrycja Dubielecka, Julie White, Yogindra Vedvyas, Cyrus V. Hedvat, Adriana Haimovitz-Friedman, Jason A. Koutcher, Janet A. Sawicki. Disruption of Abi1/Hssh3bp1 expression induces prostatic intraepithelial neoplasia in the conditional Abi1/Hssh3bp1 KO mice [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A51.