Targeted inactivation of ß1 integrin induces ß3 integrin switching that drives breast cancer metastasis by TGF-ß

Molecular biology of the cell

PubMedID: 24006485

Parvani JG, Galliher-Beckley AJ, Schiemann BJ, Schiemann WP. Targeted inactivation of ß1 integrin induces ß3 integrin switching that drives breast cancer metastasis by TGF-ß. Mol Biol Cell. 2013;.
Mammary tumorigenesis and epithelial-mesenchymal transition (EMT) programs cooperate in converting transforming growth factor-ß (TGF-ß) from a suppressor to a promoter of breast cancer metastasis. Although previous reports have associated ß1 and ß3 integrins with TGF-ß stimulation of EMT and metastasis, the functional interplay and plasticity exhibited by these adhesion molecules in shaping the oncogenic activities of TGF-ß remain unknown. We demonstrate that inactivation of ß1 integrin impaired TGF-ß from stimulating the motility of normal and malignant mammary epithelial cells (MECs), as well as elicited robust compensatory expression of ß3 integrin solely in malignant MECs, but not in their normal counterparts. Compensatory ß3 integrin expression also (i) enhanced the growth of malignant MECs in rigid and compliant 3D-organotypic cultures, and (ii) restored the induction of the EMT phenotypes by TGF-ß. Importantly, compensatory expression of ß3 integrin rescued the growth and pulmonary metastasis of ß1 integrin-deficient 4T1 tumors in mice, a process that was prevented by both genetic depletion or functional inactivation of ß3 integrin. Collectively, our findings demonstrate that inactivation of ß1 integrin elicits metastatic progression via a ß3 integrin-specific mechanism, indicating that dual ß1 and ß3 integrin targeting is necessary to alleviate metastatic disease in breast cancer patients.