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Targeted inactivation of ?1 integrin induces ?3 integrin switching, which drives breast cancer metastasis by TGF-?.

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

PROVIDER: S-EPMC3814150 | BioStudies |

REPOSITORIES: biostudies

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