Survivin-targeting miRNAs in erbB3 promotion of erbB2-positive breast cancer

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DESCRIPTION (provided by applicant): Amplification and/or overexpression of erbB2 (or HER2/neu) occur in approximately 25-30% of invasive breast cancer and are significantly associated with a worse prognosis. Mechanistic studies suggest that increased resistance to treatment and enhanced metastatic potential are the major mechanism by which erbB2 contributes to breast tumorigenesis. However, erbB2 does not act in isolation. Another closely related receptor erbB3 frequently co-expresses and interacts with erbB2 to activate the oncogenic signaling, such as PI-3K/Akt pathway and others, and subsequently promote breast cancer progression. Nonetheless, the crucial downstream mediators of erbB3 signaling in erbB2-positive (erbB2+) breast cancer remain elusive. We have reported that the erbB3/PI-3K/Akt signaling confers paclitaxel resistance in erbB2+ breast cancer cells via specific upregulation of Survivin, a vital inhibitor of apoptosis. Our recent studies on the underlying mechanism discover that elevated expression of erbB3 decreases and inhibition of erbB3 signaling with shRNA, a blocking antibody (Ab), or an Akt inhibitor increases the expression of two Survivin-targeting miRNAs, miR-203 and miR-542-3p in erbB2+ breast cancer cells. Interestingly, both miR-203 and miR-542-3p have been identified as tumor suppressive miRNAs and are frequently downregulated due to promoter methylation in various cancers, including breast cancer. Bioinformatic analysis suggests that in addition to Survivin, these two miRNAs also co-target a cohort of critical genes, such as ABCG2, ZEB2, and Snail, responsible for drug resistance and tumor metastasis. Thus, we hypothesize that activation of erbB3 signaling promotes erbB2+ breast cancer progression via epigenetic silencing of the Survivin-targeting miR-203 and miR-542-3p. This proposal aims to explore the molecular basis of erbB3 signaling-induced reduction of miR-203/miR-542-3p, and determine the anti-tumor activity of miRNA-replacement therapy in combination with paclitaxel against erbB2+ breast cancer.