MicroRNAs (miRNAs) are crucial post-transcriptional regulators of gene expression, and their deregulation contributes to many aspects of cancer development and progression. Thus, miRNAs provide insight into oncogenic mechanisms and represent promising targets for new therapeutic approaches. A type of cancer that is still in urgent need of improved treatment options is triple negative breast cancer (TNBC). Therefore, we aimed to characterize a novel miRNA with a potential role in TNBC. Based on a previous study, we selected miR-4646-5p, a miRNA with a still unknown function in breast cancer. We discovered that higher expression of miR-4646-5p in TNBC patients is associated with better survival. In vitro assays showed that miR-4646-5p overexpression reduces growth, proliferation, and migration of TNBC cell lines, whereas inhibition had the opposite effect. Furthermore, we found that miR-4646-5p inhibits the tube formation ability of endothelial cells, which may indicate anti-angiogenic properties. By whole transcriptome analysis, we not only observed that miR-4646-5p downregulates many oncogenic factors, like tumor-promoting cytokines and migration- and invasion-related genes, but were also able to identify a direct target, the GRAM domain-containing protein 1B (GRAMD1B). GRAMD1B is involved in cellular cholesterol transport and its knockdown phenocopied the growth-reducing effects of miR-4646-5p. We thus conclude that GRAMD1B may partly contribute to the diverse tumor-suppressive effects of miR-4646-5p in TNBC.

BioTechMed Graz 8010 Graz Austria

Department for Biomedical Research Medical University of Graz 8036 Graz Austria

Department of Biology Faculty of Medicine and Central European Institute of Technology Masaryk University 625 00 Brno Czech Republic

Department of Medical and Surgical Sciences University of Bologna 40126 Bologna Italy

Division of Hematology Department of Internal Medicine Medical University of Graz 8036 Graz Austria

Division of Molecular Biology and Biochemistry Gottfried Schatz Research Center for Cell Signaling Metabolism and Aging Medical University of Graz 8010 Graz Austria

Division of Oncology Department of Internal Medicine Medical University of Graz 8036 Graz Austria

Research Unit for Non Coding RNA and Genome Editing Medical University of Graz 8010 Graz Austria

Translational Oncology 2 Med Clinics Hematology and Oncology 86156 Augsburg Germany

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