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. Mi...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13058-023-01716-2 |
| _version_ | 1797451009620967424 |
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| author | Katharina Jonas Felix Prinz Manuela Ferracin Katarina Krajina Barbara Pasculli Alexander Deutsch Tobias Madl Beate Rinner Ondrej Slaby Christiane Klec Martin Pichler |
| author_facet | Katharina Jonas Felix Prinz Manuela Ferracin Katarina Krajina Barbara Pasculli Alexander Deutsch Tobias Madl Beate Rinner Ondrej Slaby Christiane Klec Martin Pichler |
| author_sort | Katharina Jonas |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T14:48:44Z |
| format | Article |
| id | doaj.art-d088562194214dca97084323852b7d66 |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-03-09T14:48:44Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-d088562194214dca97084323852b7d662023-11-26T14:37:45ZengBMCBreast Cancer Research1465-542X2023-10-0125111710.1186/s13058-023-01716-2MiR-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 capivasertibKatharina Jonas0Felix Prinz1Manuela Ferracin2Katarina Krajina3Barbara Pasculli4Alexander Deutsch5Tobias Madl6Beate Rinner7Ondrej Slaby8Christiane Klec9Martin Pichler10Division of Oncology, Department of Internal Medicine, Medical University of GrazDivision of Oncology, Department of Internal Medicine, Medical University of GrazDepartment of Experimental, Diagnostic and Specialty Medicine, University of BolognaTranslational Oncology, II. Med Clinics Hematology and OncologyFondazione IRCCS Casa Sollievo della Sofferenza Laboratorio di OncologiaDivision of Hematology, Department of Internal Medicine, Medical University of GrazDivision of Molecular Biology and Biochemistry, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of GrazDepartment for Biomedical Research, Medical University of GrazDepartment of Biology, Faculty of Medicine and Central European Institute of Technology, Masaryk UniversityDivision of Oncology, Department of Internal Medicine, Medical University of GrazDivision of Oncology, Department of Internal Medicine, Medical University of GrazAbstract 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.https://doi.org/10.1186/s13058-023-01716-2microRNA (miRNA)Triple negative breast cancer (TNBC)Phosphatidylinositol-4-phosphate 5-kinase type 1 gamma (PIP5K1C)AKT signalingCapivasertib |
| spellingShingle | Katharina Jonas Felix Prinz Manuela Ferracin Katarina Krajina Barbara Pasculli Alexander Deutsch Tobias Madl Beate Rinner Ondrej Slaby Christiane Klec Martin Pichler 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 Breast Cancer Research microRNA (miRNA) Triple negative breast cancer (TNBC) Phosphatidylinositol-4-phosphate 5-kinase type 1 gamma (PIP5K1C) AKT signaling Capivasertib |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | microRNA (miRNA) Triple negative breast cancer (TNBC) Phosphatidylinositol-4-phosphate 5-kinase type 1 gamma (PIP5K1C) AKT signaling Capivasertib |
| url | https://doi.org/10.1186/s13058-023-01716-2 |
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