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Reversion of the Malignant Phenotype of Human Breast Cells in Three-Dimensional Culture and In Vivo by Integrin Blocking Antibodies
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In a recently developed human breast cancer model, treatment of tumor cells in a 3-dimensional culture with inhibitory β1-integrin antibody or its Fab fragments led to a striking morphological and functional reversion to a normal phenotype. A stimulatory β1-integrin antibody proved to be ineffective. The newly formed reverted acini re-assembled a basement membrane and re-established E-cadherin–catenin complexes, and re-organized their cytoskeletons. At the same time they downregulated cyclin D1, upregulated p21cip,waf-1, and stopped growing. Tumor cells treated with the same antibody and injected into nude mice had significantly reduced number and size of tumors in nude mice. The tissue distribution of other integrins was also normalized, suggesting the existence of intimate interactions between the different integrin pathways as well as adherens junctions. On the other hand, nonmalignant cells when treated with either α6 or β4 function altering antibodies continued to grow, and had disorganized colony morphologies resembling the untreated tumor colonies. This shows a significant role of the α6/β4 heterodimer in directing polarity and tissue structure. The observed phenotypes were reversible when the cells were disassociated and the antibodies removed. Our results illustrate that the extracellular matrix and its receptors dictate the phenotype of mammary epithelial cells, and thus in this model system the tissue phenotype is dominant over the cellular genotype.
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“As a result, 2D cell culture tests sometimes provide misleading and nonpredictive data for in vivo responses. 1-3”
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Metadata
- Authors
- Weaver, V. M., Petersen, O. W., Wang, F., Larabell, C. A., Briand, P., Damsky, C., & Bissell, M. J.
- Affiliations
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Weaver, V.M.
- ORCID
- Weaver, V.M.
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 1997-04-07
- Volume
- 137
- Issue
- 1
- Pages
- 231-245
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2139858
- OpenAlex
- W1541555963
- Cited by
- 1,483
- References
- 98
- Citations by year
- 2026: 19 · 2025: 27 · 2024: 19 · 2023: 51 · 2022: 38 · 2021: 49 · 2020: 50 · 2019: 51 · 2018: 62 · 2017: 63 · 2016: 63 · 2015: 58 · 2014: 64 · 2013: 63 · 2012: 89
- FWCI
- 13.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Cell Biology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- University of North Texas Digital Library (University of North Texas) (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Lawrence Berkeley National Laboratory
- Funders
- U.S. Department of Defense (DE-AC02-05CH11231)
- U.S. Department of Energy (-AC02-05CH11231, DE-AC03-?, 05CH11231, DE AC02 05CH11231, DE-AC03-SF00098, DE-AC02-)
- Sundhed og Sygdom, Det Frie Forskningsråd
- National Institutes of Health (DE-AC02–05CH11231)
- Medical Research Council (DE-AC02-05CH11231)
- National Cancer Institute (CA-64786, R37CA064786, R01CA064786)
- Lawrence Berkeley National Laboratory (AC02‐05CH11231, DE-AC02-05CH11231, 05CH11231)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- beta1 integrin, integrin blocking antibodies, breast cancer, 3D cell culture, E-cadherin-catenin complex, adherens junctions, extracellular matrix, mammary epithelial cells, cyclin D1, p21, tumor growth inhibition, cell polarity, tissue structure
- MeSH terms
- Animals, Antibodies, Monoclonal, Basement Membrane, Binding, Competitive, Breast Neoplasms, Cell Division, Extracellular Matrix, Female, Fluorescent Antibody Technique, Genotype, Humans, Immunoglobulin Fab Fragments, Phenotype, Transformation, Genetic, Tumor Cells, Cultured, Signal Transduction, Antigens, CD, Integrin beta1, Integrin beta4, Mice, Rats
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