Therapeutic targeting of integrin αvβ6 in breast cancer

Kate M. Moore, Gareth J. Thomas, Stephen W. Duffy, Jane Warwick, Rhian Gabe, Patrick Chou, Ian O. Ellis, Andrew R. Green, Syed Haider, Kellie Brouilette, Antonio Saha, Sabari Vallath, Rebecca Bowen, Claude Chelala, Diana Eccles, William J. Tapper, Alastair M. Thompson, Phillip Quinlan, Lee Jordan, Cheryl GillettAdam Brentnall, Shelia Violette, Paul H. Weinreb, Jane Kendrew, Simon T. Barry, Ian R. Hart, J. Louise Jones, John F. Marshall

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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.

Original languageEnglish
Article numberdju169
JournalJournal of the National Cancer Institute
Volume106
Issue number8
DOIs
Publication statusPublished - Aug 2014

Keywords

  • Animals
  • Antibodies, Monoclonal, Humanized/pharmacology
  • Antigens, Neoplasm/drug effects
  • Antineoplastic Agents/pharmacology
  • Antineoplastic Combined Chemotherapy Protocols/pharmacology
  • Breast Neoplasms/drug therapy
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Immunohistochemistry
  • Integrins/drug effects
  • Kaplan-Meier Estimate
  • Mice
  • Mice, SCID
  • Molecular Targeted Therapy/methods
  • Receptor, ErbB-2/genetics
  • Trastuzumab
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

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