title: A novel double-negative feedback loop between miR-489 and the HER2-SHP2-MAPK signaling axis regulates breast cancer cell proliferation and tumor growth.
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.
authors.affiliation: Department of Biological Science, University of South Carolina, Columbia, SC, USA.|Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA.
authors.forename: Yogin
authors.initials: Y
authors.lastname: Patel
authors.affiliation: Department of Biological Science, University of South Carolina, Columbia, SC, USA.|Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA.
authors.forename: Nirav
authors.initials: N
authors.lastname: Shah
authors.affiliation: Department of Surgery, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Ji Shin
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, USA.
authors.forename: Eleni
authors.initials: E
authors.lastname: Markoutsa
authors.affiliation: Master of Science in Biomedical Sciences Program, Des Moines University, Des Moines, IA, USA.
authors.forename: Chunfa
authors.initials: C
authors.lastname: Jie
authors.affiliation: Department of Biological Science, University of South Carolina, Columbia, SC, USA.|Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA.
authors.forename: Shou
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Biological Science, University of South Carolina, Columbia, SC, USA.|Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Botbyl
authors.affiliation: Department of Biological Science, University of South Carolina, Columbia, SC, USA.|Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA.
authors.forename: David
authors.initials: D
authors.lastname: Reisman
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, USA.
authors.forename: Peisheng
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Biological Science, University of South Carolina, Columbia, SC, USA.|Center for Colon Cancer Research, University of South Carolina, Columbia, SC, USA.
authors.forename: Hexin
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D009368:Neoplasm Transplantation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D035683:MicroRNAs; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D018719:Erb-b2 Receptor Tyrosine Kinases; C552418:MIRN489 microRNA, human; C508053:ERBB2 protein, human; C516724:PTPN11 protein, human
keywords: HER2; breast cancer; miR-489; microRNA; tumor suppressor