Abstract

Human epidermal growth factor receptor 2 (HER2 or ErBb2) is a receptor tyrosine kinase overexpressed in 20-30% of breast cancers and associated with poor prognosis and outcome. Dysregulation of several microRNAs (miRNAs) plays a key role in breast cancer progression and metastasis. In this study, we screened and identified miRNAs dysregualted in HER2-positive breast cancer cells. Our molecular study demonstrated that miR-489 was specifically downregulated by the HER2-downstream signaling, especially through the MAPK pathway. Restoration or overexpression of miR-489 in HER2-positive breast cancer cells significantly inhibited cell growth in vitro and decreased the tumorigenecity and tumor growth in xenograft mice. Mechanistically, we found that overexpression of miR-489 led to the decreased levels of HER2 and SHP2 and thus attenuated HER2-downstream signaling. Furthermore, we for the first time demonstrated that HER2 is a direct target of miR-489 and therefore HER2-SHP2-MAPK and miR-489 signaling pathways form a mutually inhibitory loop. Using quantitative real-time PCR analysis and Fluorescent in situ hybridization technique (FISH), we found that miR-489 was expressed at significantly lower level in tumor tissues compared to the adjacent normal tissues. Downregulation of miR-489 in breast cancers was associated with aggressive tumor phenotypes. Overall, our results define a double-negative feedback loop involving miR-489 and the HER2-SHP2-MAPK signaling axis that can regulate breast cancer cell proliferation and tumor progression and might have therapeutic relevance for HER2-positive breast cancer.

Highlights

  • Breast cancer is a heterogeneous disease with several subtypes identified by unique molecular signatures [1,2,3]

  • Using quantitative real-time PCR analysis and Fluorescent in situ hybridization technique (FISH), we found that miR-489 was expressed at significantly lower level in tumor tissues compared to the adjacent normal tissues

  • We identified miR-489 as one of the candidate miRNAs whose expression was downregulated by HER2 downstream Mitogen activated protein kinase (MAPK) signaling and for the first time showed that miR-489 directly binds to the 3’-UTR of HER2 mRNA and down-regulates its expression

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Summary

Introduction

Breast cancer is a heterogeneous disease with several subtypes identified by unique molecular signatures [1,2,3]. 30% of total breast cancer patients overexpress human epidermal growth factor receptor 2 (ErbB2 or HER2) [4,5,6,7] It is well documented in the literature that overexpression of HER2 promotes aggressive tumor phenotype, increases metastasis and decreases overall survival of patients [3, 6, 8]. Aberrant expression of specific miRNAs by HER2 leads to the enhanced resistance to chemotherapeutic drugs [13,14,15,16]. It still remains largely unknown how HER2 promotes tumor progression via regulation of specific microRNAs

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