Abstract
Abstract Nkx3.1 is a homeodomain-containing transcription factor essential for prostate development and differentiation while loss mediates prostate tumor initiation. In mice, conditional loss of Nkx3.1 results in prostatic epithelial hyperplasia and prostatic intraepithelial neoplasia (PIN) formation. This increases the susceptibility of mice with compound mutations to the development of invasive adenocarcinoma. Human clinical data suggests that loss of Nkx3.1 and Myc overexpression are strongly correlated with increased tumor stage. Furthermore, Myc overexpressing transgenic mice lose Nkx3.1 in the PIN to carcinoma transition suggesting that Nkx3.1 loss is distinct and may provide a selective growth advantage. To further evaluate the cooperation between Nkx3.1 and Myc, we generated transgenic mice with prostate specific loss of Nkx3.1 and Myc overexpression. These mice contain a latent, Cre-activatable Myc allele and Nkx3.1 floxed alleles. Prostate specific Cre results in concurrent deletion of Nkx3.1 and activation of Myc. We have found that the young trigenic mice show advanced lesions compared to controls. High grade prostate intraepithelial neoplasia (HGPIN) was evident as early as 15 weeks of age. By 35 weeks of age, these mice show multi-focal HGPIN lesions with micro-invasive cancer. An increase in proliferation and a modest increase in apoptosis are also seen. Complementary prostate regeneration studies further support this progressive phenotype. We hypothesize that Nkx3.1 and Myc are cooperating to promote prostate tumorigenesis by regulating important cancer genes. Future studies are being conducted to identify the mechanism of cooperation between Nkx3.1 and Myc. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2401. doi:10.1158/1538-7445.AM2011-2401
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