Abstract P4-07-02: MicroRNA 204 mediated negative regulation of the IGF2R promotes breast cancer progression and is a potential mechanism driving breast cancer disparity
Authors: Findlay VJ , Nogueira LM , Turner DP , Kramer RM , Rosenzweig SA , Rosen JM , Watson DK 
Published: August 2014

Abstract
Breast cancer (BC) is a worldwide health issue as it represents the leading cause of cancer in women and the second leading cause of cancer-related mortality in women, with an increasing incidence. In the US, African American (AA) women have a significantly higher rate of mortality due to BC compared to Caucasian American (CA) women. It is becoming increasingly apparent that racial disparity in cancer exists due to molecular differences in tumor biology as well as, or in addition to, socioeconomic and standard of care issues. Sparse information exists regarding the molecular mechanisms that promote BC health disparity therefore, a greater understanding of the risk factors and biological links associated with BC, will significantly impact AA women. Our studies have identified a race specific mechanistic link between microRNA-204 (miR-204) and the Insulin-like Growth Factor-2 Receptor. MicroRNAs are small non-coding RNAs that function to inhibit gene expression through translational repression. Our published studies identified miR-204 as a novel oncomir and we recently identified IGF2R as a direct target. The IGF2R has been proposed to be a tumor suppressor gene in several cancers including breast cancer. We show that over-expression of miR-204 results in a decrease in IGF2R protein levels. We propose that the inhibition of IGF2R allows IGF-2 to bind the IGF1R leading to hyperactivation of this pathway which results in increased proliferation, migration and invasion, processes that are required for tumor progression. Indeed, we show that miR-204 expression results in the activation of the IGF1R/IRS-1/ERK pathway together with an increase in proliferation, migration and invasion. Published studies have shown that exogenous expression of activated IGF1R increases migration in non-transformed breast cells. We have shown that exogenous expression of miR-204 also increases migration in these cells. However, when miR-204 and IGF1R are both exogenously expressed no additional increase in migration was observed, suggesting that mIR-204 mediated increase in migration is through activation of the IGF1R pathway. Reduced IGF2R expression correlates with poor patient prognosis in BC patients and a recent study showed significantly higher levels of IGF2R in CA compared to AA tumor samples, suggesting that decreased IGF2R expression may contribute to BC disparity. We examined serum from BC patients and found elevated levels of miR-204 in AA compared to CA women. Circulating miRNAs can serve as accessible biomarkers for diagnosis & prognosis and may define a novel area of potential therapeutic intervention to reduce BC disparity. Our data also suggest that miR-204 mediated inhibition of IGF2R could be a potential biological mechanism driving BC disparity. A major hurdle to the identification of biological mechanisms conferring cancer health disparity is a lack of suitable experimental models with which to investigate race specific differences in tumor biology. We have developed a unique 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.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-07-02.