MiR-4649-5p acts as a tumor-suppressive microRNA in triple negative breast cancer by direct interaction with PIP5K1C, thereby potentiating growth-inhibitory effects of the AKT inhibitor capivasertib

Abstract

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.

miRNAs Related to Immune Checkpoint Inhibitor Response: A Systematic Review

“…In contrast, miR-4649-3p and miR-615-3p overexpression was observed in stage IV melanoma patients who progressed after anti-CTLA-4 (Ipilimumab), anti-PD-1 (Nivolumab or Pembrolizumab), or the combination of Ipilimumab and Nivolumab [42]. miR-4649-3p has been identified as a tumor suppressor in triple-negative breast cancer by targeting PIP5K1C, an Akt activator [76], while miR-615 targets the NK group 2 (NKG2) family receptor or TNF-α from immune cells, leading to diminished cytotoxic activity against tumor cells [77].…”

Molecular Mechanisms and Clinical Implications of Noncoding RNAs in Cancer

“…The associations between seven novel miRNAs (miR-13844-5p, miR-590-5p, miR-3345-5p, miR-13172-3p, miR-7154-5p, miR-766-3p, and miR-8861-5p) and 81 targets were also revealed as potential biomarkers for CRC. Jonas [15] also conducted a cytological functional verification of miR-4646-5p via three-dimensional breast cancer spheroid expression screening for the first time. miR-4646-5p mainly acts as a tumor suppressor in triple-negative breast cancer (TNBC) and targets the cholesterol transporter GRAMD1B to regulate the growth, proliferation, and migration of TNBC cells and the formation of endothelial cells in vitro and to induce apoptosis.…”