TY - JOUR
T1 - HIF-1 alpha Overexpression in Ductal Carcinoma In Situ of the Breast in BRCA1 and BRCA2 Mutation Carriers
AU - van der Groep, Petra
AU - van Diest, Paul J.
AU - Smolders, Yvonne H. C. M.
AU - Ausems, Margreet G. E. M.
AU - van der Luijt, Rob B.
AU - Menko, Fred H.
AU - Bart, Joost
AU - de Vries, Elisabeth G. E.
AU - van der Wall, Elsken
PY - 2013/2/8
Y1 - 2013/2/8
N2 - Recent studies have revealed that BRCA1 and BRCA2 germline mutation-related breast cancers show frequent overexpression of hypoxia inducible factor-1 alpha (HIF-1 alpha), 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-1 alpha 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-1 alpha, CAIX and Glut-1 in DCIS and available invasive carcinoma lesions of 32 BRCA1, 16 BRCA2 and 77 non-BRCA mutation-related cases. HIF-1 alpha 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-1 alpha, 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-1 alpha, 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.
AB - Recent studies have revealed that BRCA1 and BRCA2 germline mutation-related breast cancers show frequent overexpression of hypoxia inducible factor-1 alpha (HIF-1 alpha), 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-1 alpha 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-1 alpha, CAIX and Glut-1 in DCIS and available invasive carcinoma lesions of 32 BRCA1, 16 BRCA2 and 77 non-BRCA mutation-related cases. HIF-1 alpha 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-1 alpha, 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-1 alpha, 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.
KW - HYPOXIA-INDUCIBLE FACTOR-1-ALPHA
KW - COMPARATIVE GENOMIC HYBRIDIZATION
KW - BASAL EPITHELIAL PHENOTYPE
KW - GROWTH-FACTOR EXPRESSION
KW - MOLECULAR CLASSIFICATION
KW - ESTROGEN-RECEPTOR
KW - REDUCES HYPOXIA
KW - HIGH PREVALENCE
KW - TUMOR-GROWTH
KW - CANCER
U2 - 10.1371/journal.pone.0056055
DO - 10.1371/journal.pone.0056055
M3 - Article
C2 - 23409121
SN - 1932-6203
VL - 8
JO - PLoS ONE
JF - PLoS ONE
IS - 2
M1 - e56055
ER -