Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer.
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-te...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2007
|
| _version_ | 1797061155764568064 |
|---|---|
| author | Tan, E Campo, L Han, C Turley, H Pezzella, F Gatter, K Harris, A Fox, S |
| author_facet | Tan, E Campo, L Han, C Turley, H Pezzella, F Gatter, K Harris, A Fox, S |
| author_sort | Tan, E |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T20:27:01Z |
| format | Journal article |
| id | oxford-uuid:2fbc794e-3acb-4a9b-925b-2f208c122d71 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:27:01Z |
| publishDate | 2007 |
| record_format | dspace |
| spelling | oxford-uuid:2fbc794e-3acb-4a9b-925b-2f208c122d712022-03-26T12:57:11ZCytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2fbc794e-3acb-4a9b-925b-2f208c122d71EnglishSymplectic Elements at Oxford2007Tan, ECampo, LHan, CTurley, HPezzella, FGatter, KHarris, AFox, S 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. |
| spellingShingle | Tan, E Campo, L Han, C Turley, H Pezzella, F Gatter, K Harris, A Fox, S Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer. |
| title | Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer. |
| title_full | Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer. |
| title_fullStr | Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer. |
| title_full_unstemmed | Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer. |
| title_short | Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer. |
| title_sort | cytoplasmic location of factor inhibiting hypoxia inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer |
| work_keys_str_mv | AT tane cytoplasmiclocationoffactorinhibitinghypoxiainduciblefactorisassociatedwithanenhancedhypoxicresponseandashortersurvivalininvasivebreastcancer AT campol cytoplasmiclocationoffactorinhibitinghypoxiainduciblefactorisassociatedwithanenhancedhypoxicresponseandashortersurvivalininvasivebreastcancer AT hanc cytoplasmiclocationoffactorinhibitinghypoxiainduciblefactorisassociatedwithanenhancedhypoxicresponseandashortersurvivalininvasivebreastcancer AT turleyh cytoplasmiclocationoffactorinhibitinghypoxiainduciblefactorisassociatedwithanenhancedhypoxicresponseandashortersurvivalininvasivebreastcancer AT pezzellaf cytoplasmiclocationoffactorinhibitinghypoxiainduciblefactorisassociatedwithanenhancedhypoxicresponseandashortersurvivalininvasivebreastcancer AT gatterk cytoplasmiclocationoffactorinhibitinghypoxiainduciblefactorisassociatedwithanenhancedhypoxicresponseandashortersurvivalininvasivebreastcancer AT harrisa cytoplasmiclocationoffactorinhibitinghypoxiainduciblefactorisassociatedwithanenhancedhypoxicresponseandashortersurvivalininvasivebreastcancer AT foxs cytoplasmiclocationoffactorinhibitinghypoxiainduciblefactorisassociatedwithanenhancedhypoxicresponseandashortersurvivalininvasivebreastcancer |