Preclinical data indicate that
alpha6beta4 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
alpha6beta4 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
alpha6beta4 integrin or Net1 expression and clinical outcome when each marker was considered individually, coexpression of alpha6beta4 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 alpha6beta4 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 alpha6beta4 and Net1 (P = 0.008) was observed, coexpression of alpha6beta4 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
alpha6beta4 integrin and Net1 could be a useful
biomarker for aggressive disease in node-positive
breast cancer patients.