Loss of <i>Igf2</i> Gene Imprinting in Murine Prostate Promotes Widespread Neoplastic Growth.

Abstract

Loss of imprinting (LOI) is an epigenetic event that relaxes an allele-specific restriction on gene expression. One gene that experiences LOI is the paracrine insulin-like growth factor <i>IGF2</i>, which occurs commonly in human prostate tissues during aging and tumorigenesis. However, the relationship between <i>IGF2</i> LOI and prostate tumorigenesis has not been established functionally. In this study, we created a mouse model with CTCF-binding site mutations at the <i>Igf2-H19</i> imprint control region that abolishes CTCF insulator activity, resulting in biallelic <i>Igf2</i> expression that mimics increased levels seen with aging-induced LOI. We found that <i>Igf2</i> LOI increased the prevalence and severity of prostatic intraepithelial neoplasia (PIN), a premalignant lesion. Engineering <i>Nkx3.1</i> deficiency into our model increased the frequency of PIN lesions in an additive fashion. Prostates harboring LOI displayed increased MAPK signaling and epithelial proliferation. In human prostate tissue arrays, we documented a positive correlation in benign tissues of IGF2 levels with phospho-ERK and phospho-AKT levels. Overall, our results establish that <i>Igf2</i> LOI is sufficient on its own to increase rates of neoplastic development in the prostate by upregulating critical cancer-associated signaling pathways. <i>Cancer Res; 77(19); 5236-47. ©2017 AACR</i>.