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MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells

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Tumor Biology

Abstract

The Runx1 transcription factor, known for its essential role in normal hematopoiesis, was reported in limited studies to be mutated or associated with human breast tumor tissues. Runx1 increases concomitantly with disease progression in the MMTV-PyMT transgenic mouse model of breast cancer. Compelling questions relate to mechanisms that regulate Runx1 expression in breast cancer. Here, we tested the hypothesis that dysregulation of Runx1-targeting microRNAs (miRNAs) allows for pathologic increase of Runx1 during breast cancer progression. Microarray profiling of the MMTV-PyMT model revealed significant downregulation of numerous miRNAs predicted to target Runx1. One of these, miR-378, was inversely correlated with Runx1 expression during breast cancer progression in mice and in human breast cancer cell lines MCF7 and triple-negative MDA-MB-231 that represent early- and late-stage diseases, respectively. MiR-378 is nearly absent in MDA-MB-231 cells. Luciferase reporter assays revealed that miR-378 binds the Runx1 3′ untranslated region (3′UTR) and inhibits Runx1 expression. Functionally, we demonstrated that ectopic expression of miR-378 in MDA-MB-231 cells inhibited Runx1 and suppressed migration and invasion, while inhibition of miR-378 in MCF7 cells increased Runx1 levels and cell migration. Depletion of Runx1 in late-stage breast cancer cells resulted in increased expression of both the miR-378 host gene PPARGC1B and pre-miR-378, suggesting a feedback loop. Taken together, our study identifies a novel and clinically relevant mechanism for regulation of Runx1 in breast cancer that is mediated by a PPARGC1B-miR-378-Runx1 regulatory pathway. Our results highlight the translational potential of miRNA replacement therapy for inhibiting Runx1 in breast cancer.

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Acknowledgments

This work was supported by the National Cancer Institute (Nos. P01 CA082834 and R03 CA167726), National Institute of Arthritis and Musculoskeletal and Skin Diseases (No. R01 AR039588), National Institute of Dental and Craniofacial Research (No. R37 DE012528), Pfizer (WS2049100), and grants from the University of Vermont Cancer Center and Lake Champlain Cancer Research Organization. The microarray research reported was supported by the National Institute of General Medical Sciences (No. P20 GM103449). The authors thank all members of our laboratories, especially Philip W. L. Tai, for valuable suggestions throughout the study. The authors are grateful to the UVM Cancer Center Advanced Genome Technologies Core, supported by UVM Cancer Center, Lake Champlain Cancer Research Organization, and the UVM College of Medicine for data pertaining to cell line authentication, as well as the Vermont Genetics Network Microarray Facility for miRNA target preparation, hybridization, and scanning processing. The authors are also grateful to the Molecular Bioinformatics Shared Resource of the University of Vermont College of Medicine for microarray data analysis. Finally, the authors thank the Advanced Genome Technologies Core Massively Parallel Sequencing Facility for sequencing data. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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  1. Department of Biochemistry & University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT, 05405, USA

    Gillian Browne, Deli Hong, Terri L. Messier, Jonathan A. R. Gordon, Nicholas H. Farina, Joseph R. Boyd, Jennifer J. VanOudenhove, Andrew W. Perez, Sayyed K. Zaidi, Janet L. Stein, Gary S. Stein & Jane B. Lian

  2. Department of Microbiology and Molecular Genetics, University of Vermont, 95 Carrigan Avenue, Burlington, VT, 05405, USA

    Julie A. Dragon

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Browne, G., Dragon, J.A., Hong, D. et al. MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells. Tumor Biol. 37, 8825–8839 (2016). https://doi.org/10.1007/s13277-015-4710-6

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