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

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Publikace nespadá pod Fakultu sportovních studií, ale pod Lékařskou fakultu. Oficiální stránka publikace je na webu muni.cz.
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JONAS Katharina PRINZ Felix FERRACIN Manuela KRAJINA Katarina PASCULLI Barbara DEUTSCH Alexander MADL Tobias RINNER Beate SLABÝ Ondřej KLEC Christiane PICHLER Martin

Rok publikování 2023
Druh Článek v odborném periodiku
Časopis / Zdroj Breast Cancer Research
Fakulta / Pracoviště MU

Lékařská fakulta

Citace
www https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-023-01716-2
Doi http://dx.doi.org/10.1186/s13058-023-01716-2
Klíčová slova microRNA (miRNA); Triple negative breast cancer (TNBC); AKT signaling; Capivasertib
Přiložené soubory
Popis BackgroundTriple 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 resultsHere, 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.ConclusionIn 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.
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