MicroRNA 204 mediated negative regulation of the IGF2R promotes breast cancer progression and is a potential mechanism driving breast cancer disparity

Abstract

In the US, African American women have a significantly higher rate of mortality due to breast cancer compared to Caucasian American women. Molecular differences in tumor biology exist between racial groups; however, their contribution to cancer disparity is not well understood. Our studies have identified a race-specific, mechanistic link between microRNA-204 and the IGF2R. The IGF2R is a tumor suppressor gene in several cancers including breast cancer and IGF2R levels are found at significantly lower levels in African American women with breast cancer when compared to their Caucasian counterparts. We observed elevated levels of miR-204 in serum of African American women with breast cancer when compared to Caucasian American women and identified IGF2R as a direct target of miR-204. We show mechanistically that miR-204 mediated inhibition of IGF2R leads to activation of the IGF1R signaling pathway resulting in increased proliferation, migration and invasion, processes that are required for tumor progression. We developed a unique doxycycline-inducible miR-204 transgenic mouse model to define in vivo the oncogenic potential of miR-204 and the mechanism and functional consequences of IGF2R loss. We observed a significant increase in tumor growth and increased metastasis in these animals when compared to non-transgenic controls. This is the first characterization of miR-204 in an in vivo model. These data support a mechanism whereby miR-204 promotes tumor aggression through the IGF2-mediated hyperactivation of the IGF1R signaling pathway in response to direct negative regulation of the tumor suppressor IGF2R and that this could be a potential mechanism promoting breast cancer disparity.