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Integrin β5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways

Oncogene volume 32, pages 3049–3058 (2013)Cite this article

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Abstract

Cancer progression, response to therapy and metastasis depend on tumor microenvironment. Integrins are cell-adhesion receptors that mediate interactions of cells with extracellular matrix. The αv-β-family of integrins contributes to tumorigenesis, response to therapy and cancer stem cell biology. Thus, understanding the function of specific integrins in cancer is critical for the development of therapeutic approaches targeting integrins. The study investigated the role of integrin β5 in breast carcinomas by depleting integrin β5 using RNA interference and reexpression of integrin β5. Depletion of integrin β5 in triple-negative breast carcinoma cells markedly reduced tumor take, growth and tumor angiogenesis, whereas reexpression of integrin β5 rescued this phenotype. Reduction in tumor angiogenesis is associated with lower expression of vascular endothelial growth factor-A in integrin β5-depleted tumors. Tumor cells deficient in integrin β5 have lower migration and proliferative capacities. Biochemical assays revealed that integrin β5 mediates the Src-focal adhesion kinase and MEK-extracellular signal-regulated kinase signaling events that operate independently, and inhibition of these pathways phenocopies integrin β5 deficiency. Breast carcinoma cells express high levels of integrin β5, whereas expression of integrin β3 is limited to stromal compartments and integrin β6 is lost in metastatic cells. Together, these findings show a critical role for integrin β5 in the tumorigenic potential of breast carcinoma cells and therapeutic targeting of integrin β5 is especially attractive for triple-negative breast carcinomas, which are refractory to most of the current therapies.

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Acknowledgements

This work was supported by NYSDOH-HSRB Peter T Rowley Breast Cancer Project and in part by RPCI Cancer Center Support Grant CA 16056. We thank Dr Irwin Gelman for his helpful discussion of the manuscript, Drs Raymond Birge, Jianmin Zhang and Yahao Bu for providing reagents and Drs Kitty De Jong and Janice Hoffmann (RPCI flow cytometry facility) for their technical help.

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  1. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA

    A Bianchi-Smiraglia, S Paesante & A V Bakin

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Correspondence to A V Bakin.

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Bianchi-Smiraglia, A., Paesante, S. & Bakin, A. Integrin β5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways. Oncogene 32, 3049–3058 (2013). https://doi.org/10.1038/onc.2012.320

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