High focal adhesion kinase expression in breast carcinoma is associated with lymphovascular invasion and triple-negative phenotype

BackgroundFocal adhesion Kinase (FAK) is a nonreceptor protein tyrosine kinase that is overexpressed in tumors and plays a significant role in tumor survival and metastasis. The purpose of the study is to perform correlation of FAK expression with patient prognostic factors using tissue microarrays (TMA) samples.MethodsWe analyzed FAK expression by immunohistochemical staining in 196 breast primary tumor samples from stage II-IV patients and in 117 metastatic tissues matched to the primary tumors using TMA that were stained with FAK monoclonal antibody.ResultsHigh FAK expression in primary tumors was associated with a younger age of patients (p = 0.033), lymphovascular invasion (p = 0.001) and with the triple-negative phenotype (p = 0.033). FAK expression in 117 metastatic tissues positively correlated with FAK expression in matched primary tumors by Spearman correlation analysis. In addition, a strong positive correlation was observed between high FAK expression and shorter overall survival and progression free survival in patients with metastatic tumors.ConclusionsThe data demonstrate a high potential for FAK as a therapeutic target, especially in triple-negative breast cancer patients with high FAK expression.

[1]  R. Weinberg,et al.  Integrin β1-focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs , 2009, Proceedings of the National Academy of Sciences.

[2]  V. Golubovskaya,et al.  Focal Adhesion Kinase Expression in Human Neuroblastoma: Immunohistochemical and Real-time PCR Analyses , 2008, Clinical Cancer Research.

[3]  B. Cieply,et al.  Mechanisms that link the oncogenic epithelial–mesenchymal transition to suppression of anoikis , 2013, Journal of Cell Science.

[4]  M. Schaller,et al.  FAK regulates biological processes important for the pathogenesis of cancer , 2003, Cancer and Metastasis Reviews.

[5]  D. Noh,et al.  Clinical significance of high focal adhesion kinase gene copy number and overexpression in invasive breast cancer , 2011, Breast Cancer Research and Treatment.

[6]  S. Sheen-Chen,et al.  An evaluation of focal adhesion kinase in breast cancer by tissue microarrays. , 2013, Anticancer research.

[7]  T. Lechertier,et al.  Focal adhesion kinase and tumour angiogenesis , 2012, The Journal of pathology.

[8]  A. Magis,et al.  A small molecule inhibitor, 1,2,4,5-benzenetetraamine tetrahydrochloride, targeting the y397 site of focal adhesion kinase decreases tumor growth. , 2008, Journal of medicinal chemistry.

[9]  Joseph Geradts,et al.  High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype , 2005, Modern Pathology.

[10]  Su Jie,et al.  FAK signaling is critical for ErbB-2/ErbB-3 receptor cooperation for oncogenic transformation and invasion , 2005, The Journal of cell biology.

[11]  D. Allred,et al.  Prognostic and predictive factors in breast cancer by immunohistochemical analysis. , 1998, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[12]  A. Magis,et al.  A novel small molecule inhibitor of FAK decreases growth of human pancreatic cancer , 2009, Cell cycle.

[13]  G. Gillespie,et al.  Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples. , 2002, Cancer research.

[14]  W. Cance,et al.  Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer , 2006, Annals of Surgical Oncology.

[15]  Thomas Hawighorst,et al.  Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis , 2001, Nature Medicine.

[16]  V. Golubovskaya,et al.  Inhibition of focal adhesion kinase and src increases detachment and apoptosis in human neuroblastoma cell lines , 2009, Molecular carcinogenesis.

[17]  L. Kornberg,et al.  Focal adhesion kinase expression in oral cancers , 1998, Head & neck.

[18]  C. Livasy,et al.  Overexpression of focal adhesion kinase in primary colorectal carcinomas and colorectal liver metastases: immunohistochemistry and real-time PCR analyses. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[19]  Xiaping He,et al.  Overexpression of focal adhesion kinase, a protein tyrosine kinase, in ovarian carcinoma , 1999, Cancer.

[20]  V. Golubovskaya,et al.  Focal Adhesion Kinase Versus p53: Apoptosis or Survival? , 2008, Science Signaling.

[21]  Chris Smith,et al.  Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response. , 2013, Endocrine-related cancer.

[22]  A. Børresen-Dale,et al.  Triple-negative breast cancer and the need for new therapeutic targets. , 2013, The American journal of pathology.

[23]  I. Ellis,et al.  The prognostic significance of lymphovascular invasion in invasive breast carcinoma , 2012, Cancer.

[24]  J. Kononen,et al.  Tissue microarrays for high-throughput molecular profiling of tumor specimens , 1998, Nature Medicine.

[25]  C. Livasy,et al.  Upregulation of focal adhesion kinase (FAK) expression in ductal carcinoma in situ (DCIS) is an early event in breast tumorigenesis , 2004, Breast Cancer Research and Treatment.

[26]  M. Eck,et al.  The FERM domain: organizing the structure and function of FAK , 2010, Nature Reviews Molecular Cell Biology.

[27]  V. Golubovskaya,et al.  Disrupting the Scaffold to Improve Focal Adhesion Kinase–Targeted Cancer Therapeutics , 2013, Science Signaling.