PYK2 promotes HER2-positive breast cancer invasion

Abstract

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 HE...

The histone H2B ubiquitin ligase RNF40 is required for HER2-driven mammary tumorigenesis

“…In addition to the central role of actin-cytoskeleton dynamics in controlling cellular migration, ROCK1, Factin and the focal adhesion kinase signaling pathway also have critical functions in suppressing apoptosis and are strongly associated with BC progression including HER2 + -BC 41,44,[54][55][56][57] . While we previously identified a role for RNF40 in suppressing apoptosis in colorectal cancer cells via expression of antiapoptotic members of the BCL2 family of proteins 19 , our current results suggest that RNF40 supports HER2 + -BC tumor viability and tumorigenic features in a distinct manner via maintenance of ROCK-dependent focal adhesion kinase signaling.…”

The synergistic effect of circRNA methylation promotes pulmonary fibrosis

“…Furthermore, METTL3 knockdown significantly reduced the induction of fibroblast activation markers (Figure 6B–E) and fibroblast migration (Figure 6F and G). Additionally, phosphorylation of PYK2, a protein related to cell migration and invasion (Al-Juboori et al , 2019; Naser et al , 2018), was also attenuated after METTL3 knockdown (Figure E9A and B). Consistently, upregulation of cell viability induced by SiO 2 was inhibited with METTL3 knockdown (Figure 6H).…”

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“…At the same time, p38 phosphorylation was greatly increased. Of note, pyk 2 (also called focal adhesion kinase 2; FAK2) is a ROS-sensitive cytoplasmic tyrosine kinase that plays a role in cellular adhesion and is conceived as a metastatic marker in various forms of human cancer [39], including breast cancer in humans [40]. Similarly, SNAIL, is a transcription factor that can be induced under DNA damage responses in breast cancer and trigger metastasis [41], although metastasis induction in MDA-MB231 cells is primarily driven by SLUG [42].…”