Caveolin-1 Knockout Mitigates Breast Cancer Metastasis to the Lungs via Integrin α3 Dysregulation.

Abstract

Caveolin-1 (Cav-1) is a critical lipid raft protein playing divergent roles as both a tumor suppressor and promoter. While its role in tumorigenesis, progression, and metastasis is recognized, explicit contribution of Cav-1 to the onset of lung metastasis from primary breast malignancies remained vague. We exhibit here, the first-ever evidence of Cav-1 knockout in epithelial cells leading to a significant reduction in lung metastasis in syngeneic mouse models of breast cancer. In vitro, Cav-1 knockout in 4T1 cells suppressed extracellular vesicles secretion, cellular motility, and MMP secretion vis-à-vis the controls. Complementing this, our in vivo analyses demonstrated a marked reduction in lung metastatic foci in mice injected with Cav-1 knockout 4T1 cells as compared to wild-type mice, which was further corroborated by mRNA profiling of the primary tumor. We discerned 21 epithelial cell migration genes exhibiting varied expression in tumors derived from Cav-1 knockout versus wild-type 4T1 cells. Correlation analysis and immunoblotting further divulged that Cav-1 regulates metastasis via integrin α3 (ITGα3). In silico protein docking anticipated an interaction between Cav-1 and ITGα3, substantiated by co-immunoprecipitation. Furthermore, ITGα3 knockdown corroborated its role in metastasis in a cell migration assay. Therefore, it can be inferred that Cav-1 plays a pivotal role in the pre-metastatic niche establishment and facilitates lung-specific cell migration.