4.8 Article

Functional Redundancy between β1 and β3 Integrin in Activating the IR/Akt/mTORC1 Signaling Axis to Promote ErbB2-Driven Breast Cancer

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

  1. Canadian Institutes of Health Research Foundation [148373]
  2. Cedars Cancer Institute fellowship
  3. McGill Integrated Cancer Research Training Program award
  4. Natural Sciences and Engineering Research Council (NSERC), Canada award
  5. Canada Research Chair in Advanced Cellular Microenvironments
  6. 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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