Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer.

Abstract

INTRODUCTION:

Hypoxia-inducible factor (HIF)-1alpha levels in invasive breast carcinoma have been shown to be an adverse prognostic indicator. Cellular HIF-1alpha activity is regulated by factor-inhibiting hypoxia-inducible factor 1 (FIH-1). In hypoxia, FIH-1 hydroxylation of Asn803 within the C-terminal transactivation domain does not occur and HIF-1alpha forms a fully active transcriptional complex. The present study investigates the role of FIH-1 in invasive breast carcinoma and its correlation with hypoxia.

METHODS:

Microarrayed tissue cores from 295 invasive carcinomas were stained for FIH-1, for HIF-1alpha and for carbonic anhydrase 9. FIH-1 expression was correlated with standard clinicopathological parameters and with the expression of the surrogate hypoxic markers HIF-1alpha and carbonic anhydrase 9.

RESULTS:

FIH-1 was positive in 239/295 (81%) tumours, 42/295 (14%) exclusively in the nucleus and 54/295 (18%) exclusively in the cytoplasm. Exclusive nuclear FIH-1 expression was significantly inversely associated with tumour grade (P = 0.02) and risk of recurrence (P = 0.04), whereas exclusive cytoplasmic FIH-1 was significantly positively associated with tumour grade (P = 0.004) and carbonic anhydrase 9 expression (P = 0.02). Patients with tumours that excluded FIH-1 from the nucleus had a significantly shorter survival compared with those with exclusive nuclear expression (P = 0.02). Cytoplasmic FIH-1 expression was also an independent poor prognostic factor for disease-free survival.

CONCLUSION:

FIH-1 is widely expressed in invasive breast carcinoma. As with other HIF regulators, its association between cellular compartmentalization and the hypoxic response and survival suggests that tumour regulation of FIH-1 is an additional important mechanism for HIF pathway activation.

• Authors: Ern Yu Tan, Leticia Campo, Cheng Han, Helen Turley, Francesco Pezzella, Kevin C Gatter, Adrian L Harris, Stephen B Fox
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 9 Issue 6 Pg. R89 ( 2007) ISSN: 1465-542X [Electronic] England
• PMID: 18096060 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Biomarkers, Tumor
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Repressor Proteins
• Transcription Factors
• Mixed Function Oxygenases
• HIF1AN protein, human
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases

Topics

• Adult
• Aged
• Aged, 80 and over
• Antigens, Neoplasm (metabolism)
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (metabolism, mortality, pathology)
• Carbonic Anhydrase IX
• Carbonic Anhydrases (metabolism)
• Cell Hypoxia
• Cytoplasm (metabolism)
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Immunohistochemistry
• Middle Aged
• Mixed Function Oxygenases
• Neoplasm Invasiveness
• Predictive Value of Tests
• Prognosis
• Repressor Proteins (metabolism)
• Survival Analysis
• Transcription Factors (metabolism)