Journal article
The highly metastatic 4T1 breast carcinoma model possesses features of a hybrid epithelial-mesenchymal phenotype
Disease models & mechanisms, Vol.17(9), dmm050771
09/04/2024
DOI: 10.1242/dmm.050771
PMCID: PMC11391819
PMID: 39104192
Appears in UI Libraries Support Open Access
Abstract
Epithelial-mesenchymal transitions (EMTs) are thought to promote metastasis via downregulation of E-cadherin and upregulation of mesenchymal markers such as N-cadherin and vimentin. Contrary to this, E-cadherin is retained in many invasive carcinomas and promotes collective cell invasion. To investigate how E-cadherin regulates metastasis, we examined the highly metastatic, E-cadherin-positive murine 4T1 breast cancer model, together with the less metastatic, 4T1-related cell lines, 4T07, 168FARN, and 67NR. We found that 4T1 cells display a hybrid-E/M phenotype with co-expression of epithelial and mesenchymal markers, while 4T07, 168FARN, and 67NR display progressively more mesenchymal phenotypes in vitro that relate inversely to their metastatic capacity in vivo. Using RNA interference and constitutive expression, we demonstrate that the expression level of E-cadherin does not determine 4T1 or 4T07 cell metastatic capacity in mice. Mechanistically, 4T1 cells possess highly dynamic, unstable cell-cell junctions and can undergo collective invasion without E-cadherin downregulation. However, 4T1 orthotopic tumors in vivo also contain subregions of EMT-like loss of E-cadherin. Thus, 4T1 cells function as a model for carcinomas with a hybrid-E/M phenotype that promotes invasion and metastasis.Epithelial-mesenchymal transitions (EMTs) are thought to promote metastasis via downregulation of E-cadherin and upregulation of mesenchymal markers such as N-cadherin and vimentin. Contrary to this, E-cadherin is retained in many invasive carcinomas and promotes collective cell invasion. To investigate how E-cadherin regulates metastasis, we examined the highly metastatic, E-cadherin-positive murine 4T1 breast cancer model, together with the less metastatic, 4T1-related cell lines, 4T07, 168FARN, and 67NR. We found that 4T1 cells display a hybrid-E/M phenotype with co-expression of epithelial and mesenchymal markers, while 4T07, 168FARN, and 67NR display progressively more mesenchymal phenotypes in vitro that relate inversely to their metastatic capacity in vivo. Using RNA interference and constitutive expression, we demonstrate that the expression level of E-cadherin does not determine 4T1 or 4T07 cell metastatic capacity in mice. Mechanistically, 4T1 cells possess highly dynamic, unstable cell-cell junctions and can undergo collective invasion without E-cadherin downregulation. However, 4T1 orthotopic tumors in vivo also contain subregions of EMT-like loss of E-cadherin. Thus, 4T1 cells function as a model for carcinomas with a hybrid-E/M phenotype that promotes invasion and metastasis.
Details
- Title: Subtitle
- The highly metastatic 4T1 breast carcinoma model possesses features of a hybrid epithelial-mesenchymal phenotype
- Creators
- Mary E HerndonMitchell Ayers - Purdue University NorthwestKatherine Gibson-Corley - University of Iowa, The University of Iowa Institute for Vision ResearchMichael K Wendt - University of Iowa, Holden Comprehensive Cancer CenterLori L Wallrath - University of Iowa, Biochemistry and Molecular BiologyMichael D Henry - University of Iowa, Molecular Physiology and BiophysicsChristopher S Stipp - University of Iowa, Biology
- Resource Type
- Journal article
- Publication Details
- Disease models & mechanisms, Vol.17(9), dmm050771
- Publisher
- The Company of Biologists
- DOI
- 10.1242/dmm.050771
- PMID
- 39104192
- PMCID
- PMC11391819
- ISSN
- 1754-8411
- eISSN
- 1754-8411
- Grant note
- Holden Comprehensive Cancer Center, University of IowaUniversity of Iowa
This research was supported by a pilot grant from the Holden Comprehensive Cancer Center, University of Iowa. Open Access funding provided by University of Iowa. Deposited in PMC for immediate release.
- Language
- English
- Electronic publication date
- 08/06/2024
- Date published
- 09/04/2024
- Academic Unit
- Molecular Physiology and Biophysics; The University of Iowa Institute for Vision Research; Pathology; Biology; Radiation Oncology; Biochemistry and Molecular Biology; Holden Comprehensive Cancer Center; University College Courses; Internal Medicine
- Record Identifier
- 9984695158402771
Metrics
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