A novel double-negative feedback loop between miR-489 and the HER2-SHP2-MAPK signaling axis regulates breast cancer cell proliferation and tumor growth
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Yogin Patel1,2,*, Nirav Shah1,2,*, Ji Shin Lee3, Eleni Markoutsa4, Chunfa Jie5, Shou Liu1,2, Rachel Botbyl1,2, David Reisman1,2, Peisheng Xu4, Hexin Chen1,2
1Department of Biological Science, University of South Carolina, Columbia, SC, USA
2Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA
3Department of Surgery, Chonnam National University, Gwangju, Republic of Korea
4Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, USA
5Master of Science in Biomedical Sciences Program, Des Moines University, Des Moines, IA, USA
*These authors have contributed equally to this work
Hexin Chen, e-mail: email@example.com
Keywords: microRNA, miR-489, HER2, breast cancer, tumor suppressor
Received: December 2, 2015 Accepted: February 11, 2016 Published: February 22, 2016
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.
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