PYK2 promotes HER2-positive breast cancer invasion

• Published in: Journal of experimental & clinical cancer research 2019-05, Vol.38 (1), p.210-210, Article 210
• Main Authors: Al-Juboori, Shaymaa Ik, Vadakekolathu, Jayakumar, Idri, Sarra, Wagner, Sarah, Zafeiris, Dimitrios, Pearson, Joshua Rd, Almshayakhchi, Rukaia, Caraglia, Michele, Desiderio, Vincenzo, Miles, Amanda K, Boocock, David J, Ball, Graham R, Regad, Tarik
• Format: Article
• Language: English
• Subjects: Antidiabetics; Apoptosis; Apoptosis - drug effects; Breast cancer; Breast cancer stem cells; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer cells; Cancer prevention; Cancer research; Cancer therapies; Cancer treatment; Care and treatment; Cell growth; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemoresistance; Diabetes; Diabetes therapy; Drug resistance; Drug Resistance, Neoplasm - genetics; Female; Focal Adhesion Kinase 2 - genetics; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic aspects; Genetic research; Humans; Kinases; Lung cancer; MCF-7 Cells; Medical research; Metformin; Metformin - adverse effects; Metformin - pharmacology; Neoplasm Invasiveness - genetics; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Phenotypes; Plasmids; Polymerase chain reaction; Proteins; Proteomics; Pure HER2 breast Cancer; PYK2/PTK2B; Receptor, ErbB-2 - genetics; Signal Transduction; Stem cells; Systematic review; Tumors; Type 2 diabetes; Wound care; Wound healing
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-019-1221-0

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. 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. 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 ce