Back to Search
Start Over
High frequency of HIF-1alpha overexpression in BRCA1 related breast cancer.
- Source :
-
Breast cancer research and treatment [Breast Cancer Res Treat] 2008 Oct; Vol. 111 (3), pp. 475-80. Date of Electronic Publication: 2007 Nov 21. - Publication Year :
- 2008
-
Abstract
- Hypoxia is a hallmark of cancer. Hypoxia inducible factor-1alpha (HIF-1alpha) is the key regulator of the hypoxia response. HIF-1alpha is overexpressed during sporadic breast carcinogenesis and correlated with poor prognosis. Little is known on the role of HIF-1alpha in hereditary breast carcinogenesis. A recent study suggests a role for BRCA1 in HIF-1alpha regulation. We therefore examined the expression of HIF-1alpha in BRCA1 related breast cancers. By immunohistochemistry we studied expression of HIF-1alpha and some of its downstream targets in 30 hereditary invasive breast cancers in comparison with 200 sporadic controls. HIF-1alpha overexpression was significantly more frequent in BRCA1 related breast cancers (27/30, 90%) than in sporadic controls (88/200, 44%) (P < 0.0001). 19/30 (63%) of BRCA1 tumors showed perinecrotic (hypoxia induced) and 8/30 (27%) a diffuse HIF-1alpha overexpression pattern, the latter more likely related to genetic alterations in oncogenes and tumor suppressor genes. In contrast, sporadic breast cancer HIF-1 expressing tumors showed an inverse ratio of perinecrotic/diffuse expression (31 vs. 69%, P = 0.0002). Glut-1 and CAIX, downstream HIF1 targets, were expressed in 27/30 (90%) and 15/21 (71%) of hereditary cases versus 54/183 (29%) and 24/183 (13%) in sporadic cases. p300 levels, necessary for HIF-1 downstream activation, were significantly higher in hereditary cases (20/21, 95%) compared to sporadic cases (91/183, 50%, P = 0.0001). In conclusion, in BRCA1 germline mutation related breast cancer, functional HIF-1alpha overexpression is seen at a much higher frequency than in sporadic breast cancer, mostly hypoxia induced. This points to an important role of hypoxia and its key regulator HIF-1alpha in hereditary breast carcinogenesis.
- Subjects :
- Breast Neoplasms genetics
Breast Neoplasms pathology
Cell Hypoxia
Female
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Humans
Necrosis
Neoplasm Invasiveness
Up-Regulation
BRCA1 Protein genetics
Breast Neoplasms chemistry
Germ-Line Mutation
Hypoxia-Inducible Factor 1, alpha Subunit analysis
Subjects
Details
- Language :
- English
- ISSN :
- 0167-6806
- Volume :
- 111
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Breast cancer research and treatment
- Publication Type :
- Academic Journal
- Accession number :
- 18030615
- Full Text :
- https://doi.org/10.1007/s10549-007-9817-z