Elevated expression of HER3, which interacts with HER2 in
breast cancer cells, confers chemoresistance via
phosphoinositide 3-kinase (PI-3K)/Akt-dependent upregulation of
Survivin. However, the underlying mechanism is not clear. Ectopic expression or specific knockdown of HER3 in HER2-overexpressing
breast cancer cells did not alter
Survivin mRNA levels and
Survivin protein stability, supporting the notion that HER3 signaling may regulate specific
miRNAs that target
Survivin to alter its protein translation. Here we showed that overexpression and specific knockdown of HER3 reduced and enhanced expression of two
Survivin-targeting
miRNAs, miR-203 and miR-542-3p, in
breast cancer cells, respectively. While the specific inhibitor of either miR-203 or miR-542-3p attenuated an anti-HER3 antibody-induced downregulation of
Survivin, inhibition of miR-542-3p exhibited a better efficacy than miR-203 inhibition did. Consistently, miR-542-3p mimic was much more effective than miR-203 mimic not only in inhibition of
Survivin, but also in enhancement of
paclitaxel-induced apoptosis in HER2-overexpressing
breast cancer cells. Moreover, the combination of miR-542-3p mimic and
paclitaxel, as compared with either agent alone, significantly inhibited in vivo
tumor growth of HER2-overexpressing
breast cancer cells. Collectively, our data indicated that the HER3/PI-3K/Akt signaling upregulates
Survivin via suppression of miR-203 and miR-542-3p. Because miR-542-3p has three binding sites on the 3'-UTR of
Survivin mRNA, its mimic was able to effectively downregulate
Survivin in vitro and in vivo. Thus, miR-542-3p-replacement
therapy is an excellent approach to overcome HER3-mediated
paclitaxel resistance and significantly enhances the antitumor activity of
paclitaxel against HER2-overexpressing
breast cancer.