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PreprintCited by 12Caveolin-1 and cellular processesMechanisms of cancer metastasisCancer Cells and Metastasis

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

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Francis, Joseph, Singh, Dhirendra, Pathak, Rashmi, Pandit, Abhishek, Ebenezer, Philip, Kumar, Sanjay, Duplooy, Alexander, White, Mary, Jambunathan, Nithya, Chintalaramulu, Naveen, Dharmakumar, Rohan·2023·Cancer Gene Therapy
DOI 10.21203/rs.3.rs-3677189/v1PMC PMC11567888

Preprint — published as 10.1038/s41417-024-00821-4 · Paper page

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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.

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Metadata

Authors
Francis, J., Singh, D., Pathak, R., Pandit, A., Ebenezer, P., Kumar, S., Duplooy, A., White, M., Jambunathan, N., Chintalaramulu, N., & Dharmakumar, R.
Affiliations
  • Louisiana State University (US)
  • Indiana University School of Medicine (US)
  • Midwestern University (US)
Corresponding author
Francis, Joseph
ORCID
Venue
Cancer Gene Therapy
Publisher
Springer Science and Business Media LLC
Published
2023-12-12
Volume
31
Issue
11
Pages
1658-1668
ISSN
0929-1903 (ISSN-L)
DOI
10.21203/rs.3.rs-3677189/v1
PMC
PMC11567888
OpenAlex
W4402331411
Cited by
12
References
1
Citations by year
2026: 5 · 2025: 5 · 2024: 2
FWCI
2.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Gene Therapy (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
Funders
National Institute of General Medical Sciences (P20GM135000)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
caveolin-1, breast cancer lung metastasis, integrin alpha3, 4T1 cells, extracellular vesicles, cell migration, matrix metalloproteinases, lipid rafts
MeSH terms
Animals, Breast Neoplasms, Cell Movement, Disease Models, Animal, Female, Humans, Lung Neoplasms, Mice, Inbred BALB C, Gene Expression Regulation, Neoplastic, Mice, Knockout, Integrin alpha3, Cell Line, Tumor, Caveolin 1, Mice, Gene Knockout Techniques

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