Abstract B046: Therapeutic targeting of integrin αvβ6 in high-risk breast cancer
Authors: Moore Kate M. , Thomas Gareth J. , Duffy Stephen W. , Warwick Jane , Gabe Rhian , Chou Patrick , Ellis Ian O. , Green Andrew R. , Haider Syed , Brouilette Kellie , Saha Antonio , Vallath Sabari , Bowen Rebecca , Chelala Claudia , Eccles Diana , Tapper William J. , Thompson Alastair M. , Quinlan Phillip , Jordan Lee , Gillett Cheryl , Brentnall Adam , Violette Sheila , Weinreb Paul , Kendrew Jane , Barry Simon T. , Hart Ian R. , Jones Louise , Marshall John F. 
Published: May 2015

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 over 2000 breast cancers by immunohistochemistry and ITGB6 mRNA expression measured in the METABRIC dataset. Overall survival was assessed using Kaplan-Meier curves and bioinformatics statistical analyses were performed in R statistical environment v2.14.1. Using antibody (264RAD; supplied by AZ-Medimmune) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in HER2 biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT assays and Transwell invasion assays and xenografts, respectively. All statistical tests were two-sided.

Results: High expression of either the mRNA or protein for the integrin subunit β6 correlated with very poor survival (HR=1.99, P=2.9x10-6) and increased metastases to distant sites (P=0.02). Co-expression of β6 and HER2 gave a worse prognosis (HR=3.43, P=4x10-12). HER2-driven invasion was mediated by αvβ6 in an Akt2-dependent manner. Monotherapy with 264RAD or trastuzumab, slowed growth of MCF-7/HER2-18 and BT-474 xenografts to a similar degree (P&lt;0.001) 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, giving hope to the 70% of women treated who have, or develop, resistance. Moreover, routine determination of the level of expression of αvβ6 on breast cancers would stratify women into higher-risk categories, requiring enhanced therapeutic intervention.

Citation Format: 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, Claudia Chelala, Diana Eccles, William J. Tapper, Alastair M. Thompson, Phillip Quinlan, Lee Jordan, Cheryl Gillett, Adam Brentnall, Sheila Violette, Paul Weinreb, Jane Kendrew, Simon T. Barry, Ian R. Hart, Louise Jones, John F. Marshall. Therapeutic targeting of integrin αvβ6 in high-risk breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B046.