Abstract 4320: The Survivin-targeting miR-542-3p overcomes erbB3 signaling-mediated chemo-resistance and enhances the antitumor activity of paclitaxel against erbB2-positive breast cancer

Abstract

Abstract Elevated expression of erbB3 interacts with erbB2 in breast cancer cells to confer chemo-resistance via induction of Survivin. However, the underlying mechanism of erbB3 signaling-induced upregulation of Survivin remains elusive. Ectopic expression or downregulation of erbB3 in erbB2-positive breast cancer cells did not alter Survivin mRNA levels and had no significant effect on Survivin protein stability. We thus hypothesize that the erbB3 signaling modulates certain miRNAs that target Survivin to influence its protein translation. Here we showed that overexpression of erbB3 decreased and specific knockdown of erbB3 enhanced expression of two Survivin-targeting miRNAs, miR-203 and miR-542-3p in breast cancer cells. While the specific inhibitor of either miR-203 or miR-542-3p clearly attenuated an anti-erbB3 antibody (Ab)-mediated reduction of Survivin, a more profound effect on Survivin expression was observed with inhibition of miR-542-3p than miR-203 inhibition. Consistently, miR-542-3p mimic was much more effective than miR-203 mimic not only to downregulate Survivin, but also to enhance paclitaxel-induced apoptosis in the otherwise paclitaxel-resistant breast cancer cells. Moreover, using a murine tumor xenografts model established from a human breast cancer cell line expressing both erbB2 and erbB3, we discovered that the combinations of miR-542-3p mimic and paclitaxel, as compared to either agent alone, significantly inhibited tumor growth in vivo. Collectively, these data demonstrate that the erbB3 signaling upregulates Survivin via inhibition of miR-203 and miR-542-3p in erbB2-positive breast cancer cells. Since miR-542-3p has three binding sites on the 3’UTR of erbB3 mRNA, the miR-542-3p mimic serves as an excellent replacement therapeutic agent to downregulate Survivin, and thereby significantly enhances the antitumor activity of paclitaxel against erbB2-positive breast cancer. Citation Format: Hui Lyu, Shuiliang Wang, Jingcao Huang, Bolun Wang, Bolin Liu. The Survivin-targeting miR-542-3p overcomes erbB3 signaling-mediated chemo-resistance and enhances the antitumor activity of paclitaxel against erbB2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4320. doi:10.1158/1538-7445.AM2017-4320