Targeting HER3 with miR-450b-3p suppresses breast cancer cells proliferation

Abstract

In breast cancer cells, heterodimerization of HER2 and HER3 plays important and dominant roles in the functionality and transformation of HER-mediated pathways, in particular the PI3K/Akt survival pathway. HER3 was considered as a major signaling hub in HER2-amplified cancers. Inhibition of HER3 expression may therefore represent a rational therapeutic approach to breast cancers where HER2/HER3-mediated signaling plays a role in tumorigenesis and progression. miRNAs exerts important roles in regulating gene expressions by binding to and repressing target mRNAs. Here we reported that miRNA-450b-3p inhibits HER3 expression by directly targeting 3′ UTR of HER3 mRNA and represses the downstream signal transductions of HER family. Overexpression of miRNA-450b-3p in SKBR3 cells inhibits cells clonogenic potential and enhances their sensitivity to trastuzumab, a monoclonal antibody that binds to the HER2 receptor, or doxorubicin through repressing proliferative signal pathways mediated by HER3/HER2/PI3K/AKT. Furthermore, we found that breast cancer patients with tumors that demonstrating upregulated HER3 (>2-fold) and downregulated miR-450b-3p (>2-fold) expressions compared with the paired adjacent non-tumorous tissues showed significantly poorer overall survival (P < 0.05). Our study identified miRNA-450b-3p as a new tumor repressor and also provided some evidences suggesting that downregulation of miR-450b-3p expression with concurrent overexpression of HER3 may serve as a prognostic biomarker for poor overall survival in breast cancer patients.

Keywords: :

• miRNA-450b-3p
• HER3
• breast cancer

Disclosure of Potential Conflicts of Interest

The authors confirm that there are no conflicts of interest.

Acknowledgments

This study was supported by National Natural Science Foundation of China (81060048).

Author Contributions

Z.Z. and T.L. conceived and designed the experiments. Z.Z., S.S., and W.M. performed the experiments. R.L. and Q.W. contributed reagents/materials/analysis tools. Z.Z., R.L., and T.L. analyzed the data. Z.Z., R.L., and T.L. wrote the paper.