title: High frequency of HIF-1alpha overexpression in BRCA1 related breast cancer.
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.
authors.affiliation: Department of Pathology, University Medical Center, 3508 GA, Utrecht, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: van der Groep
authors.forename: Alwin
authors.initials: A
authors.lastname: Bouter
authors.forename: Fred H
authors.initials: FH
authors.lastname: Menko
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D015687:Cell Hypoxia; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis*; D009336:Necrosis; D009361:Neoplasm Invasiveness; D015854:Up-Regulation
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit