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.
Highlights
Hereditary breast cancer accounts for about 5% of all breast cancers in women and is primarily caused by a germline mutation in one of the BRCA genes
To find clues whether changes in hypoxia related proteins is an early event in BRCA mutation-related carcinogenesis, we evaluated hypoxia inducible factor-1a (HIF-1a) expression in BRCA1 and BRCA2 mutationrelated ductal carcinoma in situ (DCIS) in relation with the accompanying invasive cancers
HIF-1a overexpression was observed in 63% (20/32) of the BRCA1, in 62% (10/16) of the BRCA2 and in 34% (26/77) of the non-BRCA mutation-related DCIS cases (p = 0.005;Table 1)
Summary
Hereditary breast cancer accounts for about 5% of all breast cancers in women and is primarily caused by a germline mutation in one of the BRCA genes. Several studies have indicated that the genetic makeup of BRCA1 and BRCA2 mutation-related breast cancer is different from that of non-BRCA mutation-related breast cancer. These differences comprise gains and losses of specific parts of chromosomes, as well as differences in protein expression [1,2,3,4,5,6,7]. Functional HIF-1a overexpression (mostly hypoxia induced) is seen at a much higher frequency in BRCA1 mutation-related invasive breast cancer than in sporadic breast cancer [32,33]. BRCA2 mutation-related invasive cancers express HIF-1a less frequently [33]
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