Caveolin-1 knockout mitigates breast cancer metastasis to the lungs via integrin α3 dysregulation in 4T1-induced syngeneic breast cancer model

Authors

• Dhirendra Pratap Singh, Indiana University School of Medicine, Indianapolis, IN
• Rashmi Pathak, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA
• Naveen Chintalaramulu, Indiana University School of Medicine, Indianapolis, IN
• Abhishek Pandit, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA
• Avinash Kumar, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA
• Philip J. Ebenezer, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA
• Sanjay Kumar, Louisiana State University, Baton Rouge, LA
• Alexander DuPlooy, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA
• Mary Evelyn White, Midwestern University, Glendale, AZ
• Nithya Jambunathan, Indiana University School of Medicine, Indianapolis, IN
• Rohan Dharmakumar, Indiana University School of Medicine, Indianapolis, IN
• Joseph Francis, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA

Document Type

Article

Publication Date

9-7-2024

Publication Title

Cancer Gene Therapy

Abstract

Caveolin-1 (Cav-1) is a critical lipid raft protein playing dual roles as both a tumor suppressor and promoter. While its role in tumorigenesis, progression, and metastasis has been recognized, the explicit contribution of Cav-1 to the onset of lung metastasis from primary breast malignancies remains unclear. Here, we present the first evidence that Cav-1 knockout in mammary epithelial cells significantly reduces lung metastasis in syngeneic breast cancer mouse models. In vitro, Cav-1 knockout in 4T1 cells suppressed extracellular vesicle secretion, cellular motility, and MMP secretion compared to controls. Complementing this, 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 cells, which was further corroborated by mRNA profiling of the primary tumor. We identified 21 epithelial cell migration genes exhibiting varied expression in tumors derived from Cav-1 knockout and wild-type 4T1 cells. Correlation analysis and immunoblotting further revealed that Cav-1 might regulate metastasis via integrin α3 (ITGα3). In silico protein docking predicted an interaction between Cav-1 and ITGα3, which was confirmed by co-immunoprecipitation. Furthermore, Cav-1 and ITGα3 knockdown corroborated its role in metastasis in the cell migration assay.

First Page

1658

Last Page

1668

DOI

10.1038/s41417-024-00821-4

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Singh, Dhirendra Pratap; Pathak, Rashmi; Chintalaramulu, Naveen; Pandit, Abhishek; Kumar, Avinash; Ebenezer, Philip J.; Kumar, Sanjay; DuPlooy, Alexander; White, Mary Evelyn; Jambunathan, Nithya; Dharmakumar, Rohan; and Francis, Joseph, "Caveolin-1 knockout mitigates breast cancer metastasis to the lungs via integrin α3 dysregulation in 4T1-induced syngeneic breast cancer model" (2024). LSU-LCMC Cancer Center Faculty Publications. 172.
https://digitalscholar.lsuhsc.edu/llcc_facpubs/172
10.1038/s41417-024-00821-4