Subcellular FIH-1 expression patterns in invasive breast cancer in relation to HIF-1α expression

Background Hypoxia Inducible Factor-1 alpha (HIF-1 alpha) expression in breast cancer is associated with a poor clinical outcome. HIF-1 alpha shows two expression patterns: the canonical poor prognosis hypoxia-related perinecrotic pattern and a diffuse expression pattern that seems to have less downstream effects and is clearly associated with poor survival. Factor-inhibiting hypoxia-inducible factor 1 (FIH-1) inhibits HIF-1 activity by hydroxylating the C-terminal trans-activation domain of the HIF-1 alpha subunit, thus preventing HIF-1 from recruiting co-activators CPB/p300, which are important for inducing the transcription of target genes. The aim of this study was to investigate the expression patterns of FIH-1 in breast cancer and evaluate the relationship between FIH-1 and HIF-1 alpha expression in breast cancer as a possible explanation for apparently less downstream effects of diffuse HIF-1 alpha expression. Methods Tissue sections from 92 consecutive invasive breast carcinomas were stained by immunohistochemistry for FIH-1, HIF-1 alpha, glucose transporter 1 (GLUT-1) and carbonic anhydrase IX (CAIX). Results 45 cases overexpressed HIF-1 alpha, 5 of which in a perinecrotic fashion while FIH-1 was positive in 73 of the 92 cases studied. Contrary to our expectations, three out of five cases with perinecrotic HIF-1 alpha expression were also positive for FIH1. Cytoplasmic FIH-1 correlated with HIF-1 alpha expression (P = 0.03) and tumor grade (P = 0.01). HIF-1 alpha overexpression predicted poorer prognosis as usual (P = 0.02). FIH expression had no additional prognostic value to HIF-1 alpha. Conclusions FIH1 is expressed in the majority of invasive breast carcinomas and shows distinct subcellular localization patterns. FIH-1 expression does not seem to explain the proposed functional differences between diffuse and perinecrotic HIF-1 alpha expression in breast cancer.