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Therapeutic targeting of integrin αvβ6 in breast cancer
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(2014) Therapeutic targeting of integrin αvβ6 in breast cancer. JNCI Journal of the National Cancer Institute, Volume 106 (Number 8). Article number 169. doi:10.1093/jnci/dju169 ISSN 0027-8874.
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Official URL: http://dx.doi.org/10.1093/jnci/dju169
Abstract
Background: Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.
Methods: Protein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student’s t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni’s Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.
Results: High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.
Conclusions: Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.
Item Type: | Journal Article | ||||||||
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Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) | ||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Clinical Trials Unit Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Integrins, Breast -- Cancer | ||||||||
Journal or Publication Title: | JNCI Journal of the National Cancer Institute | ||||||||
Publisher: | Oxford University Press | ||||||||
ISSN: | 0027-8874 | ||||||||
Official Date: | August 2014 | ||||||||
Dates: |
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Volume: | Volume 106 | ||||||||
Number: | Number 8 | ||||||||
Article Number: | Article number 169 | ||||||||
DOI: | 10.1093/jnci/dju169 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||
Date of first compliant deposit: | 27 December 2015 | ||||||||
Date of first compliant Open Access: | 27 December 2015 | ||||||||
Funder: | Breast Cancer Campaign, Medical Research Council (Great Britain) (MRC) | ||||||||
Grant number: | BCC 2008 May PR32 (BCC), G0800825 (MRC) |
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