PYK2 promotes HER2-positive breast cancer invasion
| Autor: | Joshua R D Pearson, Shaymaa Ik. Al-Juboori, Michele Caraglia, Rukaia Almshayakhchi, Sarra Idri, David J. Boocock, Amanda K. Miles, Graham Ball, Jayakumar Vadakekolathu, Sarah Wagner, Tarik Regad, Vincenzo Desiderio, Dimitrios Zafeiris |
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| Přispěvatelé: | Al-Juboori, S. I. K., Vadakekolathu, J., Idri, S., Wagner, S., Zafeiris, D., Pearson, J. R. D., Almshayakhchi, R., Caraglia, M., Desiderio, V., Miles, A. K., Boocock, D. J., Ball, G. R., Regad, T. |
| Rok vydání: | 2019 |
| Předmět: |
Proteomics
0301 basic medicine Cancer Research Receptor ErbB-2 Apoptosis Pure HER2 breast Cancer Stem cell marker MCF-7 Cell 0302 clinical medicine Cell Movement Breast cancer stem cell skin and connective tissue diseases biology Cell migration lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Metformin Breast cancer stem cells Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis MCF-7 Cells Neoplastic Stem Cells Female Stem cell Breast Neoplasm Chemoresistance Human Signal Transduction medicine.drug Breast Neoplasms PYK2/PTK2B lcsh:RC254-282 03 medical and health sciences Breast cancer medicine Humans Neoplasm Invasiveness Cell Proliferation Neoplasm Invasivene business.industry Research CD44 Apoptosi Proteomic Cancer medicine.disease Focal Adhesion Kinase 2 030104 developmental biology Drug Resistance Neoplasm biology.protein Cancer research Neoplastic Stem Cell business |
| Zdroj: | Journal of Experimental & Clinical Cancer Research, Vol 38, Iss 1, Pp 1-14 (2019) Journal of Experimental & Clinical Cancer Research : CR |
| ISSN: | 1756-9966 |
| Popis: | Background Metformin, a biguanide, is one of the most commonly prescribed treatments for type 2 diabetes and has recently been recommended as a potential drug candidate for advanced cancer therapy. Although Metformin has antiproliferative and proapoptotic effects on breast cancer, the heterogenous nature of this disease affects the response to metformin leading to the activation of pro-invasive signalling pathways that are mediated by the focal adhesion kinase PYK2 in pure HER2 phenotype breast cancer. Methods The effect of metformin on different breast cancer cell lines, representing the molecular heterogenicity of the disease was investigated using in vitro proliferation and apoptosis assays. The activation of PYK2 by metformin in pure HER2 phenotype (HER2+/ER−/PR-) cell lines was investigated by microarrays, quantitative real time PCR and immunoblotting. Cell migration and invasion PYK2-mediated and in response to metformin were determined by wound healing and invasion assays using HER2+/ER−/PR- PYK2 knockdown cell lines. Proteomic analyses were used to determine the role of PYK2 in HER2+/ER−/PR- proliferative, migratory and invasive cellular pathways and in response to metformin. The association between PYK2 expression and HER2+/ER−/PR- patients’ cancer-specific survival was investigated using bioinformatic analysis of PYK2 expression from patient gene expression profiles generated by the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) study. The effect of PYK2 and metformin on tumour initiation and invasion of HER2+/ER−/PR- breast cancer stem-like cells was performed using the in vitro stem cell proliferation and invasion assays. Results Our study showed for the first time that pure HER2 breast cancer cells are more resistant to metformin treatment when compared with the other breast cancer phenotypes. This drug resistance was associated with the activation of PTK2B/PYK2, a well-known mediator of signalling pathways involved in cell proliferation, migration and invasion. The role of PYK2 in promoting invasion of metformin resistant HER2 breast cancer cells was confirmed through investigating the effect of PYK2 knockdown and metformin on cell invasion and by proteomic analysis of associated cellular pathways. We also reveal a correlation between high level of expression of PYK2 and reduced survival in pure HER2 breast cancer patients. Moreover, we also report a role of PYK2 in tumour initiation and invasion-mediated by pure HER2 breast cancer stem-like cells. This was further confirmed by demonstrating a correlation between reduced survival in pure HER2 breast cancer patients and expression of PYK2 and the stem cell marker CD44. Conclusions We provide evidence of a PYK2-driven pro-invasive potential of metformin in pure HER2 cancer therapy and propose that metformin-based therapy should consider the molecular heterogeneity of breast cancer to prevent complications associated with cancer chemoresistance, invasion and recurrence in treated patients. Electronic supplementary material The online version of this article (10.1186/s13046-019-1221-0) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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