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β1 Integrin Inhibition Dramatically Enhances Radiotherapy Efficacy in Human Breast Cancer Xenografts
Open accessAbstract
β1 Integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of β1 integrin signaling. We previously showed that β1 integrin inhibitory antibodies (e.g., AIIB2) enhance apoptosis and decrease growth in human breast cancer cells in three-dimensional laminin-rich extracellular matrix (lrECM) cultures and in vivo. Here, we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used three-dimensional lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in three-dimensional lrECM. Colonies were assayed for apoptosis and β1 integrin/Akt signaling pathways were evaluated using Western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in three-dimensional lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down-regulating Akt in breast cancer colonies in three-dimensional lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared with either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We previously showed that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo. [Cancer Res 2008;68(11):4398–405]
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“Antibodies against integrins β1, β6 and β8 were shown to selectively impair TGF-β1 activation85,313–315”
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Metadata
- Authors
- Park, C. C., Zhang, H. J., Yao, E. S., Park, C. J., & Bissell, M. J.
- Affiliations
- University of California, San Francisco (US)
- Lawrence Berkeley National Laboratory (US)
- Venue
- Cancer Research
- Published
- 2008-06-01
- Volume
- 68
- Issue
- 11
- Pages
- 4398-4405
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3719863
- OpenAlex
- W1968324001
- Cited by
- 220
- References
- 43
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 8 · 2023: 10 · 2022: 12 · 2021: 15 · 2020: 9 · 2019: 10 · 2018: 12 · 2017: 14 · 2016: 13 · 2015: 13 · 2014: 20 · 2013: 19 · 2012: 18
- FWCI
- 8.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- 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)
- Funders
- U.S. Department of Defense (DE-AC02-05CH11231)
- U.S. Department of Energy (-AC02-05CH11231, DE-AC03-?, AC03-76SF00098, DEAC03-76SF00098, 05CH11231, DE AC02 05CH11231, DE-AC02-)
- National Institutes of Health (DE-AC02–05CH11231, NIH P50, DE-AC03- 76SF00098)
- University of California, San Francisco
- National Cancer Institute (R01CA124891, CA64786-09, CA-58207, R37CA064786, P50CA058207, R01CA064786, CA CA58207-08, DE-AC02-05CH11231)
- Biological and Environmental Research (05CH11231, DE-AC02 − 05CH11231, AC02-05CH11231)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- beta1 integrin, radiotherapy, breast cancer, Akt signaling, radioresistance (biology), apoptosis, MCF-7 xenografts, tumor growth inhibition, radiosensitization
- MeSH terms
- Breast, Breast Neoplasms, Cell Line, Cell Separation, Humans, Transplantation, Heterologous, Blotting, Western, Treatment Outcome, Apoptosis, Microscopy, Confocal, Integrin beta1, In Situ Nick-End Labeling, Cell Proliferation
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