Hypoxia-inducible factor 1α is closely linked to an aggressive phenotype in breast cancer

Purpose The aim of this study is to clarify characteristics of invasive breast cancer with expression of Hypoxia-induced factor 1 alpha (HIF-1 alpha) which is induced by hypoxia and signal transduction of growth factors. Experimental Design We examined, by immunohistochemical analysis, the expression of HIF-1 alpha in normal breast tissue, benign disorders and breast cancer. In invasive breast cancer, we investigated the correlation between expression of HIF-1 alpha and clinicopathological and biological factors. We also studied the prognostic value of HIF-1 alpha in breast cancer. Results HIF-1 alpha was mainly detected in tumor cell nuclei. In the 171 cases of invasive breast cancer examined, nuclear HIF-1 alpha expression was detected in 63 (36.8%) cases. Immunoreactive nuclear HIF-1 alpha was correlated with tumor size (p = 0.0013), lymph node metastasis (p = 0.0005), tumor stage (p = 0.0031) and histological grade (p = 0.0074). Elevated HIF-1 alpha levels was also associated with hormone receptor negativity (p = 0.0025), HER2 overexpression (p = 0.0053), high Ki67 labeling index (p = 0.0002), increased levels of VEGF (p < 0.0001), COX-2 overexpression (p = 0.0029) and increased nuclear p53 (p = 0.0048). In terms of the possible use of HIF-1 alpha as a prognostic indicator, patients who had increased HIF-1 alpha levels in their tumor showed shorter disease-free survival (DFS) (p < 0.0001) and overall survival (OS) (p = 0.0002) than those lacking HIF-1 alpha in univariate analysis. In multivariate analysis of DFS and OS, HIF-1 alpha was identified an independent prognostic factor. Conclusions These findings suggest that HIF-1 alpha was closely linked to an aggressive phenotype in breast cancer. It may be useful to study the expression of HIF-1 alpha using immunohistochemical analysis for better understanding of the tumor characteristics of breast cancer.