HIF-1a Overexpression in Ductal Carcinoma In Situ of the Breast in BRCA1 and BRCA2 Mutation Carriers

Recent studies have revealed that BRCA1 and BRCA2 germline mutation-related breast cancers show frequent overexpression of hypoxia inducible factor-1a (HIF-1a), 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-1a 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-1a, CAIX and Glut-1 in DCIS and available invasive carcinoma lesions of 32 BRCA1, 16 BRCA2 and 77 non-BRCA mutation-related cases. HIF-1a 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-1a, 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, th