title: HIF-1α overexpression in ductal carcinoma in situ of the breast in BRCA1 and BRCA2 mutation carriers.
abstract: Recent studies have revealed that BRCA1 and BRCA2 germline mutation-related breast cancers show frequent overexpression of hypoxia inducible factor-1α (HIF-1α), the key regulator of the hypoxia response. However, the question remained whether hypoxia is a late stage bystander or a true carcinogenetic event in patients with hereditary predisposition. We therefore studied HIF-1α overexpression in ductal carcinoma in situ (DCIS), an established precursor of invasive breast cancer.We used immunohistochemistry to examine the expression of the hypoxia markers HIF-1α, CAIX and Glut-1 in DCIS and available invasive carcinoma lesions of 32 BRCA1, 16 BRCA2 and 77 non-BRCA mutation-related cases. HIF-1α expression was detected in 63% of BRCA1 and 62% of BRCA2 as compared to 34% of non-BRCA mutation-related DCIS cases (p = 0.005). CAIX overexpression was present in 56% of BRCA1 and 44% of BRCA2 as compared to 6% of non-BRCA mutation-related DCIS cases (p = 0.000). Glut-1 overexpression was observed in 59% of BRCA1, 75% of BRCA2 and 67% of non-BRCA mutation-related DCIS cases (p = 0.527). Overall, HIF-1α, CAIX and Glut-1 expression in BRCA mutation-related DCIS matched the expression in the accompanying invasive cancers in 60% or more of cases. In non-BRCA mutation-related cases the expression of the hypoxia markers in DCIS matched the expression in the invasive part in 46% or more of the cases.Although BRCA1 and BRCA2 germline mutation-related invasive breast cancers are different in many ways, the hypoxia-related proteins HIF-1α, CAIX and Glut-1 are expressed in both DCIS and invasive lesions of BRCA1 and BRCA2 mutation carriers. This suggests that hypoxia may already play a role in the DCIS stage of BRCA1 and BRCA2 germline mutation related breast carcinogenesis, and may also drive cancer progression. Hypoxia-related proteins are therefore putative targets for therapy and molecular imaging for early detection and monitoring therapy response in BRCA mutation patients.
authors: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. p.vandergroep@umcutrecht.nl
authors: Petra
authors: P
authors: van der Groep
authors: Paul J
authors: PJ
authors: van Diest
authors: Yvonne H C M
authors: YH
authors: Smolders
authors: Margreet G E M
authors: MG
authors: Ausems
authors: Rob B
authors: RB
authors: van der Luijt
authors: Fred H
authors: FH
authors: Menko
authors: Joost
authors: J
authors: Bart
authors: Elisabeth G E
authors: EG
authors: de Vries
authors: Elsken
authors: E
authors: van der Wall
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit