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Therapeutic targeting of integrin αvß6 in breast cancer.
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, Claude; Eccles, Diana; Tapper, William J; Thompson, Alastair M; Quinlan, Phillip; Jordan, Lee; Gillett, Cheryl; Brentnall, Adam; Violette, Shelia; Weinreb, Paul H; Kendrew, Jane; Barry, Simon T; Hart, Ian R; Jones, J Louise; Marshall, John F.
Afiliação
  • Moore KM; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Thomas GJ; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Duffy SW; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Warwick J; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Gabe R; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Chou P; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Ellis IO; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Green AR; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Haider S; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Brouilette K; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Saha A; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Vallath S; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Bowen R; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Chelala C; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Eccles D; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Tapper WJ; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Thompson AM; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Quinlan P; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Jordan L; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Gillett C; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Brentnall A; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Violette S; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Weinreb PH; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Kendrew J; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Barry ST; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Hart IR; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Jones JL; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
  • Marshall JF; Affiliations of authors: Centre for Tumour Biology (KMM, GJT, KB, AS, SV, RB, IRH, JLJ, JFM), Cancer Screening Evaluation Group (SWD, JW, RG, PC), and Molecular Oncology and Imaging (SH, CC), John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, UK; Department of
J Natl Cancer Inst ; 106(8)2014 Aug.
Article em En | MEDLINE | ID: mdl-24974129
ABSTRACT

BACKGROUND:

Integrin αvß6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvß6 has yet to be elucidated in breast cancer.

METHODS:

Protein expression of integrin subunit beta6 (ß6) 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 ß6 in breast cell lines, the role of αvß6 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 ß6 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 ß6 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 αvß6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Integrinas / Receptor ErbB-2 / Terapia de Alvo Molecular / Anticorpos Monoclonais Humanizados / Antígenos de Neoplasias / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Integrinas / Receptor ErbB-2 / Terapia de Alvo Molecular / Anticorpos Monoclonais Humanizados / Antígenos de Neoplasias / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article