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Summary: 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 β1 and β3 integrin during breast cancer progression. Although ablation of β1 or β3 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. β1/β3 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. : Using a mouse model of ErbB2-driven breast cancer, Bui et al. demonstrate a functional redundancy between two integrin subunits, β1 and β3, during mammary tumorigenesis. Mechanistically, both extracellular matrix (ECM) and integrin receptors regulate insulin receptor (IR) activity to promote the Akt/mTORC1 signaling axis, a crucial pathway to malignant transformation. Keywords: ECM stiffness, ErbB2, breast cancer, insulin receptor, integrin, transgenic model, Akt, mTORC1 |
