Purpose. HIF-1alpha levels in breast carcinoma have been shown to be an adverse prognostic indicator. Cellular HIF-1alpha activity is regulated by factor inhibiting HIF (FIH)-1. In hypoxia FIH-1 hydroxylation of Asn803 within the C-terminal transactivation domain does not occur allowing HIF-1alpha to associate with its cofactors to form a fully active transcriptional complex. This study investigates the role of FIH-1 in invasive breast carcinoma and its correlation with hypoxia.
Experimental Design. Microarrayed tissue cores from 295 invasive carcinomas were stained for FIH-1, HIF-1alpha and CA9. FIH-1 expression was correlated with clinicopathological parameters, HIF-1alpha and CA9.
Results. FIH-1 was positive in both the cytoplasm and nucleus in 143/295 (48%) of tumors, exclusively in the nucleus in 42/295 (14%), exclusively in the cytoplasm in 54 /295 (18%) and negative in 56/295 (19%). Exclusive nuclear FIH-1 expression was significantly inversely associated with tumor grade (P = 0.04) and CA9 (P = 0.04) whereas exclusive cytoplasmic FIH-1 was significantly positively associated with tumor grade (P = 0.04). Survival analysis demonstrated a significantly shorter survival in patients with tumors that excluded FIH-1 from the nucleus (exclusive cytoplasmic and no FIH-1 expression) compared with exclusive nuclear expression (P = 0.02). FIH-1 expression was found to be an independent poor prognostic factor for disease-free survival with exclusive cytoplasmic expression and nuclear FIH-1 expression being associated with a shorter (P = 0.04) and longer (P = 0.07) disease-free survival respectively
Conclusions. Although FIH-1 is widely expressed in invasive breast carcinomas, its association in the cytoplasm with an enhanced hypoxic response and longer survival of patients who retain nuclear expression, suggests that FIH-1 inhibition of HIF-1alpha activity occurs primarily within the nuclear compartment.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA