BACKGROUND: Triple negative breast cancer (TNBC) is a particularly aggressive and difficult-to-treat subtype of breast cancer that requires the development of novel therapeutic strategies. To pave the way for such developments it is essential to characterize new molecular players in TNBC. MicroRNAs (miRNAs) constitute interesting candidates in this regard as they are frequently deregulated in cancer and contribute to numerous aspects of carcinogenesis. METHODS AND RESULTS: Here, we discovered that miR-4649-5p, a miRNA yet uncharacterized in breast cancer, is associated with better overall survival of TNBC patients. Ectopic upregulation of the otherwise very low endogenous expression levels of miR-4646-5p significantly decreased the growth, proliferation, and migration of TNBC cells. By performing whole transcriptome analysis and physical interaction assays, we were able to identify the phosphatidylinositol phosphate kinase PIP5K1C as a direct target of miR-4649-5p. Downregulation or pharmacologic inhibition of PIP5K1C phenocopied the growth-reducing effects of miR-4649-5p. PIP5K1C is known to play an important role in migration and cell adhesion, and we could furthermore confirm its impact on downstream PI3K/AKT signaling. Combinations of miR-4649-5p upregulation and PIP5K1C or AKT inhibition, using the pharmacologic inhibitors UNC3230 and capivasertib, respectively, showed additive growth-reducing effects in TNBC cells. CONCLUSION: In summary, miR-4649-5p exerts broad tumor-suppressive effects in TNBC and shows potential for combined therapeutic approaches targeting the PIP5K1C/PI3K/AKT signaling axis.

BioTechMed Graz Graz Austria

Department for Biomedical Research Medical University of Graz Graz Austria

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

Department of Experimental Diagnostic and Specialty Medicine University of Bologna Bologna Italy

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

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

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

Fondazione IRCCS Casa Sollievo della Sofferenza Laboratorio di Oncologia San Giovanni Rotondo FG Italy

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

Translational Oncology 2 Med Clinics Hematology and Oncology Augsburg Germany

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