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Theranostics 2020; 10(1):50-61. doi:10.7150/thno.36274 This issue Cite

Research Paper

Theranostic application of miR-429 in HER2+ breast cancer

Claudia Cava^1*, Chiara Novello^1*, Cristina Martelli², Alessia Lo Dico¹, Luisa Ottobrini^1,2, Francesca Piccotti^1,3, Marta Truffi⁴, Fabio Corsi^3,4,5, Gloria Bertoli^1✉, Isabella Castiglioni¹

1. Institute of Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR), Via F.Cervi 93, 20090 Segrate-Milan, Milan, Italy.
2. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
3. Laboratory of Nanomedicine and Molecular Imaging, Istituti Clinici Scientifici Maugeri IRCCS, via Maugeri 4, 27100, Pavia, Italy.
4. Department of Biomedical and Clinical Sciences “L. Sacco”, Università degli studi di Milano, via G. B. Grassi 74, 20157 Milano, Italy.
5. Breast Unit, Surgery Department, Istituti Clinici Scientifici Maugeri IRCCS, via Maugeri 4, 27100, Pavia, Italy.
* These authors contributed equally to this work

✉ Corresponding author: Tel: +390221717542. Email: gloria.bertolicnr.it

Abstract

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 HIF1α pathway by directly targeting VHL mRNA, a molecule important for the degradation of HIF1α. 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.

Keywords: Theranostics, HER2+ breast cancer, microRNAs, diagnosis, therapeutic tool

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