CoChat
Sign Up
Cited by 12Caveolin-1 and cellular processesMechanisms of cancer metastasisCancer Cells and Metastasis

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

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

Open access
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, Francis, Joseph·2024·Cancer Gene Therapy
DOI 10.1038/s41417-024-00821-4PMC PMC11567888

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41417-024-00821-4

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 63

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33. · DOI · Paper page
  2. Cava E, Marzullo P, Farinelli D, Gennari A, Saggia C, Riso S, et al. Breast cancer diet “BCD”: a review of healthy dietary patterns to prevent breast cancer recurrence and reduce mortality. Nutrients. 2022;14:476. · DOI
  3. Schick J, Ritchie RP, Restini C. Breast cancer therapeutics and biomarkers: past, present, and future approaches. Breast Cancer. 2021;15:1178223421995854. · DOI
  4. Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther. 2020;5:28. · DOI
  5. Dillekas H, Rogers MS, Straume O. Are 90% of deaths from cancer caused by metastases? Cancer Med. 2019;8:5574–6. · DOI
  6. Chen W, Hoffmann AD, Liu H, Liu X. Organotropism: new insights into molecular mechanisms of breast cancer metastasis. NPJ Precis Oncol. 2018;2:1–12. · DOI
  7. Huang QY, Liu GF, Qian XL, Tang LB, Huang QY, Xiong LX. Long non-coding RNA: dual effects on breast cancer metastasis and clinical applications. Cancers. 2019;11:1802. · DOI
  8. Luo H, Tu G, Liu Z, Liu M. Cancer-associated fibroblasts: a multifaceted driver of breast cancer progression. Cancer Lett. 2015;361:155–63. · DOI
  9. Guo Y, Ji X, Liu J, Fan D, Zhou Q, Chen C, et al. Effects of exosomes on pre-metastatic niche formation in tumors. Mol Cancer. 2019;18:39. · DOI
  10. Eric D, Young LL, Behbod F, Welch DR. Fundamental relationships between cancer stem cells, the cancer stem cell niche and metastasis. Bentham Sci. 2016; 3–23. · DOI
  11. Wani NA. Abstract 1166: CXCR7-mediated signaling axis regulates breast cancer growth and metastasis by modulating tumor microenvironment. Cancer Res. 2014;74:1166. · DOI
  12. Min W. Abstract 129: AIP1 suppresses tumor metastasis by regulating tumor microenvironment and metastatic niche. Cancer Res. 2014;74:129. · DOI
  13. Brena D, Huang MB, Bond V. Extracellular vesicle-mediated transport: reprogramming a tumor microenvironment conducive with breast cancer progression and metastasis. Transl Oncol. 2022;15:101286. · DOI
  14. Qian XL, Pan YH, Huang QY, Shi YB, Huang QY, Hu ZZ, et al. Caveolin-1: a multifaceted driver of breast cancer progression and its application in clinical treatment. Onco Targets Ther. 2019;12:1539–52. · DOI
  15. Ketteler J, Klein D. Caveolin-1, cancer and therapy resistance. Int J Cancer. 2018;143:2092–104. · DOI
  16. Diaz-Valdivia NI, Calderon CC, Diaz JE, Lobos-Gonzalez L, Sepulveda H, Ortiz RJ, et al. Anti-neoplastic drugs increase caveolin-1-dependent migration, invasion and metastasis of cancer cells. Oncotarget. 2017;8:111943–65. · DOI
  17. Karam JA, Lotan Y, Roehrborn CG, Ashfaq R, Karakiewicz PI, Shariat SF. Caveolin‐1 overexpression is associated with aggressive prostate cancer recurrence. Prostate. 2007;67:614–22. · DOI
  18. Low JY, Laiho M. Caveolae-associated molecules, tumor stroma, and cancer drug resistance: current findings and future perspectives. Cancers. 2022;14:589. · DOI
  19. Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Daumer KM, Milliman JN, Chiavarina B, et al. Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: implications for breast cancer and DCIS therapy with autophagy inhibitors. Cell Cycle. 2010;9:2423–33. · DOI
  20. Du C, Chen L, Zhang H, Wang Z, Liu W, Xie X, et al. Caveolin-1 limits the contribution of BKCa channel to MCF-7 breast cancer cell proliferation and invasion. Int J Mol Sci. 2014;15:20706–22. · DOI
  21. Godina C, Chandran VI, Barbachowska M, Tryggvadottir H, Nodin B, Visse E, et al. Interplay between Caveolin-1 and body and tumor size affects clinical outcomes in breast cancer. Transl Oncol. 2022;22:101464. · DOI
  22. Sotgia F, Martinez-Outschoorn UE, Howell A, Pestell RG, Pavlides S, Lisanti MP. Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol. 2012;7:423–67. · DOI
  23. Shi Y-B, Li J, Lai X-N, Jiang R, Zhao R-C, Xiong L-X. Multifaceted roles of caveolin-1 in lung cancer: a new investigation focused on tumor occurrence, development and therapy. Cancers. 2020;12:291. · DOI
  24. Singh DD, Lee H-J, Yadav DK. Recent clinical advances on long non-coding RNAs in triple-negative breast cancer. Cells. 2023;12:674. · DOI
  25. Wang Y, Li Y, Zhong J, Li M, Zhou Y, Lin Q, et al. Tumor-derived Cav-1 promotes pre-metastatic niche formation and lung metastasis in breast cancer. Theranostics. 2023;13:1684–97. · DOI
  26. Yang H, Guan L, Li S, Jiang Y, Xiong N, Li L, et al. Mechanosensitive caveolin-1 activation-induced PI3K/Akt/mTOR signaling pathway promotes breast cancer motility, invadopodia formation and metastasis in vivo. Oncotarget. 2016;7:16227–47. · DOI
  27. Godina C, Tryggvadottir H, Bosch A, Borgquist S, Belting M, Isaksson K, et al. Caveolin-1 genotypes as predictor for locoregional recurrence and contralateral disease in breast cancer. Breast Cancer Res Treat. 2023;199:335–47. · DOI
  28. Sloan EK, Stanley KL, Anderson RL. Caveolin-1 inhibits breast cancer growth and metastasis. Oncogene. 2004;23:7893–7. · DOI
  29. Burrows AD, Restall C, Sloan EK, Anderson RL. Abstract 1486: The contribution of stromal caveolin-1 to breast cancer metastasis. Cancer Res. 2012;72:1486. · DOI
  30. Jungwhoi L, Jungsul L, Chulhee C, Jae Hoon K. Blockade of integrin α3 attenuates human pancreatic cancer via inhibition of EGFR signalling. Sci Rep. 2019;9:2793. · DOI
  31. Yu H, Yang K, Lufei Z, Tianyu H, Xiaohu Z, Yingcai Y, et al. High expression of ITGA3 promotes proliferation and cell cycle progression and indicates poor prognosis in intrahepatic cholangiocarcinoma. Biomed Res Int. 2018;2018:2352139.
  32. Zhang Q, Zhang S, Chen J, Xie Z. The interplay between integrins and immune cells as a regulator in cancer immunology. Int J Mol Sci. 2023;24:6170. · DOI
  33. Hu X, Villodre ES, Woodward WA, Debeb BG. Modeling brain metastasis via tail-vein injection of inflammatory breast cancer cells. JoVE. 2021;168:e62249.
  34. Thies KA, Steck S, Knoblaugh SE, Sizemore ST. Pathological analysis of lung metastasis following lateral tail-vein injection of tumor cells. JoVE. 2020;159:e61270.
  35. Laskowski RA, Jablonska J, Pravda L, Varekova RS, Thornton JM. PDBsum: structural summaries of PDB entries. Protein Sci. 2018;27:129–34. · DOI
  36. Rose PW, Prlic A, Altunkaya A, Bi C, Bradley AR, Christie CH, et al. The RCSB protein data bank: integrative view of protein, gene and 3D structural information. Nucleic Acids Res. 2017;45:D271–81. · DOI
  37. Pierce BG, Wiehe K, Hwang H, Kim BH, Vreven T, Weng Z. ZDOCK server: interactive docking prediction of protein-protein complexes and symmetric multimers. Bioinformatics. 2014;30:1771–3. · DOI
  38. Singh DP, Begum R, Kaur G, Bagam P, Kambiranda D, Singh R, et al. E-cig vapor condensate alters proteome and lipid profiles of membrane rafts: impact on inflammatory responses in A549 cells. Cell Biol Toxicol. 2021;37:773–93. · DOI
  39. Wu PH, Gilkes DM, Phillip JM, Narkar A, Cheng TW, Marchand J, et al. Single-cell morphology encodes metastatic potential. Sci Adv. 2020;6:eaaw6938. · DOI · Paper page
  40. Kleiner DE, Stetler-Stevenson WG. Matrix metalloproteinases and metastasis. Cancer Chemother Pharm. 1999;43:S42–51. · DOI
  41. Lechuga S, Amin PH, Wolen AR, Ivanov AI. Adducins inhibit lung cancer cell migration through mechanisms involving regulation of cell-matrix adhesion and cadherin-11 expression. Biochim Biophys Acta Mol Cell Res. 2019;1866:395–408. · DOI
  42. Yu G, Wang L-G, Han Y, He Q-Y. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics. 2012;16:284–7. · DOI · Paper page
  43. Pijuan J, Barcelo C, Moreno DF, Maiques O, Siso P, Marti RM, et al. In vitro cell migration, invasion, and adhesion assays: from cell imaging to data analysis. Front Cell Dev Biol. 2019;7:107. · DOI
  44. Lee H, Carnino JM, Jin Y. Caveolin-1 regulates extracellular vesicle-miRNA packaging. Aging. 2019;11:8733–5. · DOI
  45. Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, Anderson RG. Caveolin, a protein component of caveolae membrane coats. Cell. 1992;68:673–82. · DOI
  46. Yamaguchi H, Takeo Y, Yoshida S, Kouchi Z, Nakamura Y, Fukami K. Lipid rafts and caveolin-1 are required for invadopodia formation and extracellular matrix degradation by human breast cancer cells. Cancer Res. 2009;69:8594–602. · DOI
  47. Gupta VK, Sharma NS, Kesh K, Dauer P, Nomura A, Giri B, et al. Metastasis and chemoresistance in CD133 expressing pancreatic cancer cells are dependent on their lipid raft integrity. Cancer Lett. 2018;439:101–12. · DOI
  48. Yu H, Shen H, Zhang Y, Zhong F, Liu Y, Qin L, et al. CAV1 promotes HCC cell progression and metastasis through Wnt/β-catenin pathway. PLoS ONE. 2014;9:e106451. · DOI
  49. Yokoi A, Yoshioka Y, Yamamoto Y, Ishikawa M, Ikeda S-i, Kato T, et al. Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer. Nat Commun. 2017;8:14470. · DOI
  50. Su JL, Yang PC, Shih JY, Yang CY, Wei LH, Hsieh CY, et al. The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell. 2006;9:209–23. · DOI
  51. Modi SJ, Kulkarni VM. Vascular endothelial growth factor receptor (VEGFR-2)/KDR inhibitors: medicinal chemistry perspective. Med Drug Discov. 2019;2:100009. · DOI
  52. Ye M, Huang T, Li J, Zhou C, Yang P, Ni C, et al. Role of CDH13 promoter methylation in the carcinogenesis, progression, and prognosis of colorectal cancer: a systematic meta-analysis under PRISMA guidelines. Medicine. 2017;96:e5956. · DOI
  53. Andreeva AV, Kutuzov MA. Cadherin 13 in cancer. Genes Chromosomes Cancer. 2010;49:775–90. · DOI
  54. Lorenzon E, Colladel R, Andreuzzi E, Marastoni S, Todaro F, Schiappacassi M, et al. MULTIMERIN2 impairs tumor angiogenesis and growth by interfering with VEGF-A/VEGFR2 pathway. Oncogene. 2012;31:3136–47. · DOI
  55. Kurozumi A, Goto Y, Matsushita R, Fukumoto I, Kato M, Nishikawa R, et al. Tumor‐suppressive micro RNA‐223 inhibits cancer cell migration and invasion by targeting ITGA 3/ITGB 1 signaling in prostate cancer. Cancer Sci. 2016;107:84–94. · DOI
  56. Idichi T, Seki N, Kurahara H, Fukuhisa H, Toda H, Shimonosono M, et al. Involvement of anti-tumor miR-124-3p and its targets in the pathogenesis of pancreatic ductal adenocarcinoma: direct regulation of ITGA3 and ITGB1 by miR-124-3p. Oncotarget. 2018;9:28849–65. · DOI
  57. Koshizuka K, Hanazawa T, Kikkawa N, Arai T, Okato A, Kurozumi A, et al. Regulation of ITGA 3 by the anti‐tumor miR‐199 family inhibits cancer cell migration and invasion in head and neck cancer. Cancer Sci. 2017;108:1681–92. · DOI
  58. Munkácsy G, Santarpia L, Győrffy B. Therapeutic potential of tumor metabolic reprogramming in triple-negative breast cancer. Int J Mol Sci. 2023;24:6945. · DOI
  59. Robb R, Kuo JC, Liu Y, Corrales-Guerrero S, Cui T, Hegazi A, et al. A novel protein-drug conjugate, SSH20, demonstrates significant efficacy in caveolin-1-expressing tumors. Mol Ther Oncolytics. 2021;22:555–64. · DOI
  60. Khongorzul P, Ling CJ, Khan FU, Ihsan AU, Zhang J. Antibody-drug conjugates: a comprehensive review. Mol Cancer Res. 2020;18:3–19. · DOI
  61. Pereira PMR, Mandleywala K, Monette S, Lumish M, Tully KM, Panikar SS, et al. Caveolin-1 temporal modulation enhances antibody drug efficacy in heterogeneous gastric cancer. Nat Commun. 2022;13:2526. · DOI
  62. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10:9–22. · DOI
  63. Hegazy M, Cohen-Barak E, Koetsier JL, Najor NA, Arvanitis C, Sprecher E, et al. Proximity ligation assay for detecting protein-protein interactions and protein modifications in cells and tissues in situ. Curr Protoc Cell Biol. 2020;89:e115. · DOI

Metadata

Authors
Singh, D. P., Pathak, R., Chintalaramulu, N., Pandit, A., Kumar, A., Ebenezer, P. J., Kumar, S., Duplooy, A., White, M. E., Jambunathan, N., Dharmakumar, R., & Francis, J.
Affiliations
  • Indiana University School of Medicine (US)
  • Louisiana State University (US)
  • Midwestern University (US)
Corresponding author
Francis, Joseph
ORCID
Venue
Cancer Gene Therapy
Publisher
Springer Science and Business Media LLC
Published
2024-09-07
Volume
31
Issue
11
Pages
1658-1668
ISSN
  • 0929-1903 (ISSN-L)
  • 1476-5500
DOI
10.1038/s41417-024-00821-4
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review