Abstract 5013: FOXP3 is an X-linked prostate tumor suppressor gene that represses MYC

Abstract

Abstract Despite clear epidemiological and genetic evidence for X-linked prostate cancer risk, all prostate cancer genes identified are autosomal. Here we report somatic inactivating mutations and deletion of the X-linked FOXP3 gene in human prostate cancer. We first evaluated expression of FOXP3 in both normal and prostate tissue and a reduced FOXP3 expression was wide-spread among prostate cancer samples. We then used fluorescence in situ hybridization (FISH) and determined the deletion of the FOXP3 in the 14% prostate cancer tissues. Our sequencing analyses identified single base-pair changes in 5/20 prostate cancer samples and these somatic mutations of the FOXP3 are functionally inactivating. Lineage-specific ablation of FoxP3 in the mouse prostate epithelial cells leads to prostate hyperplasia and prostate intraepithelial neoplasia. The targeted mutation of the FoxP3 in prostate tissue is sufficient to initiate the process of prostate cancer development. In both normal and malignant prostate tissues, FOXP3 is both necessary and sufficient to transcriptionally repress cMYC, the most commonly over-expressed oncogene in prostate cancer as well as among the aggregates of other cancers. FOXP3 is the first X-linked prostate tumor suppressor in the male. Since the male has only one X chromosome, our data represents a new paradigm of “single-genetic-hit” inactivation-mediated carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5013.