Journal
THERANOSTICS
Volume 10, Issue 1, Pages 50-61Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.36274
Keywords
Theranostics; HER2+breast cancer; microRNAs; diagnosis; therapeutic tool
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Funding
- Italian Ministry of University and Research (MIUR) SYSBIONET-Italian ROADMAP ESFRI Infrastructures
- Departments of Excellence
- Italian Ministry of Education, University and Research (MIUR)
- INTEROMICS flagship project (Interomics) [PB05]
- National Research Council CUP [B91JI2000190001]
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Human epidermal growth factor receptor 2 (HER2) is overexpressed/amplified in one third of breast cancers (BCs), and is associated with the poorer prognosis and the higher metastatic potential in BC. Emerging evidences highlight the role of microRNAs (miRNAs) in the regulation of several cellular processes, including BC. Methods: Here we identified, by in silico approach, a group of three miRNAs with central biological role (high degree centrality) in HER2+ BC. We validated their dysregulation in HER2+ BC and we analysed their functional role by in vitro approaches on selected cell lines and by in vivo experiments in an animal model. Results: We found that their expression is dysregulated in both HER2+ BC cell lines and human samples. Focusing our study on the only upregulated miRNA, miR-429, we discovered that it acts as an oncogene and its upregulation is required for HER2+ cell proliferation. It controls the metastatic potential of HER2+ BC subtype by regulating migration and invasion of the cell. Conclusions: In HER2+ BC oncogenic miR-429 is able to regulate HIF1 alpha pathway by directly targeting VHL mRNA, a molecule important for the degradation of HIF1 alpha. The overexpression of miR-429, observed in HER2+ BC, causes increased proliferation and migration of the BC cells. More important, silencing miR-429 succeeds in delaying tumor growth, thus miR-429 could be proposed as a therapeutic probe in HER2+ BC tumors.
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