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Coexpression of 6β4 Integrin and Guanine Nucleotide Exchange Factor Net1 Identifies Node-Positive Breast Cancer Patients at High Risk for Distant Metastasis

Departments of ¹ Pathology, ² Radiation Oncology, and ³ Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center; ⁴ Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas; and ⁵ Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

Requests for reprints: Michael Z. Gilcrease, Department of Pathology, Box 85 M. D. Anderson Cancer Center 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-9928; Fax: 713-792-4341. E-mail: mgilcrease{at}mdanderson.org

Preclinical data indicate that 6β4 integrin signaling through Ras homolog gene family, member A, plays an important role in tumor cell motility. The objective of this study was to determine whether the combined expression of 6β4 integrin and neuroepithelioma transforming gene 1 (Net1), a guanine nucleotide exchange factor specific for Ras homolog gene family member A, is associated with adverse clinical outcome in breast cancer patients. Immunohistochemical expression of each protein was evaluated in a tumor tissue microarray prepared from the primary tumors of 94 node-positive patients with invasive breast carcinoma treated with total mastectomy and doxorubicin-based chemotherapy without radiation with a median follow-up of 12.5 years. Associations between staining results and multiple clinicopathologic variables were investigated. Although there was no significant association between 6β4 integrin or Net1 expression and clinical outcome when each marker was considered individually, coexpression of 6β4 and Net1 was associated with decreased distant metastasis–free survival (P = 0.030). In the subset of patients with hormone receptor–positive tumors, coexpression of 6β4 and Net1 was associated with a decrease in distant metastasis–free and overall survival (P < 0.001 and P = 0.006, respectively). Although an association between human epidermal growth factor receptor 2 expression and coexpression of 6β4 and Net1 (P = 0.008) was observed, coexpression of 6β4 and Net1 (hazard ratio, 1.63; P = 0.02) and lymphovascular invasion (hazard ratio, 2.35; P = 0.02) were the only factors independently associated with the development of distant metastasis in multivariate analysis. These findings suggest that coexpression of 6β4 integrin and Net1 could be a useful biomarker for aggressive disease in node-positive breast cancer patients. (Cancer Epidemiol Biomarkers Prev 2009;18(1):80–6)