Breast Cancer Cells in Three-dimensional Culture Display an Enhanced Radioresponse after Coordinate Targeting of Integrin α5β1 and Fibronectin
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Abstract
Tactics to selectively enhance cancer radioresponse are of great interest. Cancer cells actively elaborate and remodel their extracellular matrix (ECM) to aid in survival and progression. Previous work has shown that β1-integrin inhibitory antibodies can enhance the growth-inhibitory and apoptotic responses of human breast cancer cell lines to ionizing radiation, either when cells are cultured in three-dimensional laminin-rich ECM (3D lrECM) or grown as xenografts in mice. Here, we show that a specific α heterodimer of β1-integrin preferentially mediates a prosurvival signal in human breast cancer cells that can be specifically targeted for therapy. 3D lrECM culture conditions were used to compare α-integrin heterodimer expression in malignant and nonmalignant cell lines. Under these conditions, we found that expression of α5β1-integrin was upregulated in malignant cells compared with nonmalignant breast cells. Similarly, we found that normal and oncofetal splice variants of fibronectin, the primary ECM ligand of α5β1-integrin, were also strikingly upregulated in malignant cell lines compared with nonmalignant acini. Cell treatment with a peptide that disrupts the interactions of α5β1-integrin with fibronectin promoted apoptosis in malignant cells and further heightened the apoptotic effects of radiation. In support of these results, an analysis of gene expression array data from breast cancer patients revealed an association of high levels of α5-integrin expression with decreased survival. Our findings offer preclinical validation of fibronectin and α5β1-integrin as targets for breast cancer therapy. Cancer Res; 70(13); 5238–48. ©2010 AACR.
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Human breast cancer cells in 3D culture overexpressed the cell adhesion molecule a5b1-integrin compared to nonmalignant cells, which can be specifically targeted for therapy.
“Nam et al. demonstrated that human breast cancer cells in 3D culture overexpressed a cell adhesion molecule a 5 b 1-integrin compared to nonmalignant cells, which can be specifically targeted for therapy. 66”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [66]
A small peptide inhibitor can prevent a5b1-integrin from binding to fibronectin, thus increasing the cell killing effect of radiation.
“They then found a small peptide inhibitor that can prevent a 5 b 1integrin from binding to fibronectin, thus increases the cell killing effect of radiation.”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [66]
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- Authors
- Nam, J.-M., Onodera, Y., Bissell, M. J., & Park, C. C.
- Affiliations
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Park, Catherine C.
- Venue
- Cancer Research
- Published
- 2010-06-30
- Volume
- 70
- Issue
- 13
- Pages
- 5238-5248
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2933183
- OpenAlex
- W2146322233
- Cited by
- 196
- References
- 51
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 9 · 2023: 7 · 2022: 11 · 2021: 9 · 2020: 15 · 2019: 11 · 2018: 21 · 2017: 18 · 2016: 11 · 2015: 15 · 2014: 14 · 2013: 20 · 2012: 14
- FWCI
- 11.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- University of North Texas Digital Library (University of North Texas) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (22700868)
- National Cancer Institute (R01CA124891, U54CA126552, U54CA143836, R37CA064786, U01CA143233, R01CA057621, U54CA112970)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- breast cancer, alpha5beta1 integrin, fibronectin, radiation response, 3D cell culture, integrin heterodimers, apoptosis, integrin-targeted therapy, patient survival
- MeSH terms
- Breast Neoplasms, Female, Fibronectins, Humans, Infrared Rays, Middle Aged, Peptides, Tumor Cells, Cultured, Up-Regulation, Gene Expression, Apoptosis, Cell Culture Techniques, Protein Isoforms, Integrin alpha5beta1, Integrin alpha5, Cell Line, Tumor, Oncogene Protein v-akt
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