Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β

Mammary tumorigenesis and epithelial-mesenchymal transition (EMT) programs cooperate in converting transforming growth factor-beta (TGF-beta) from a suppressor to a promoter of breast cancer metastasis. Although previous reports associated beta 1 and beta 3 integrins with TGF-beta stimulation of EMT and metastasis, the functional interplay and plasticity exhibited by these adhesion molecules in shaping the oncogenic activities of TGF-beta remain unknown. We demonstrate that inactivation of beta 1 integrin impairs TGF-beta from stimulating the motility of normal and malignant mammary epithelial cells (MECs) and elicits robust compensatory expression of beta 3 integrin solely in malignant MECs, but not in their normal counterparts. Compensatory beta 3 integrin expression also 1) enhances the growth of malignant MECs in rigid and compliant three-dimensional organotypic cultures and 2) restores the induction of the EMT phenotypes by TGF-beta. Of importance, compensatory expression of beta 3 integrin rescues the growth and pulmonary metastasis of beta 1 integrin-deficient 4T1 tumors in mice, a process that is prevented by genetic depletion or functional inactivation of beta 3 integrin. Collectively our findings demonstrate that inactivation of beta 1 integrin elicits metastatic progression via a beta 3 integrin-specific mechanism, indicating that dual beta 1 and beta 3 integrin targeting is necessary to alleviate metastatic disease in breast cancer patients.