Journal
CELL REPORTS
Volume 29, Issue 3, Pages 589-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.09.004
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Funding
- Canadian Institutes of Health Research Foundation [148373]
- Cedars Cancer Institute fellowship
- McGill Integrated Cancer Research Training Program award
- Natural Sciences and Engineering Research Council (NSERC), Canada award
- Canada Research Chair in Advanced Cellular Microenvironments
- Canada Research Chair in Molecular Oncology
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Integrin receptors coordinate cell adhesion to the extracellular matrix (ECM) to facilitate many cellular processes during malignant transformation. Despite their pro-tumorigenic roles, therapies targeting integrins remain limited. Here, we provide genetic evidence supporting a functional redundancy between beta 1 and beta 3 integrin during breast cancer progression. Although ablation of beta 1 or beta 3 integrin alone has limited effects on ErbB2-driven mammary tumorigenesis, deletion of both receptors resulted in a significant delay in tumor onset with a corresponding impairment in lung metastasis. Mechanistically, stiff ECM cooperates with integrin receptors to recruit insulin receptors (IRs) to focal adhesion through the formation of integrin/IR complexes, thereby preventing their lysosomal degradation. beta 1/beta 3 integrin-deficient tumors that eventually emerged exhibit impaired Akt/mTORC1 activity. Murine and human breast cancers exhibiting enhanced integrin-dependent activity also display elevated IR/Akt/mTORC1 signaling activity. Together, these observations argue that integrin/IR crosstalk transduces mechanical cues from the tumor microenvironment to promote ErbB2-dependent breast cancer progression.
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