HIF-1α 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-1α (HIF-1α), the key regulator of the hypoxia response. However, the question remained whether hypoxia is a late stage bystander or a true carcinogeneti...

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Published in:PloS one 2013-02, Vol.8 (2), p.e56055
Main Authors: van der Groep, Petra, van Diest, Paul J, Smolders, Yvonne H C M, Ausems, Margreet G E M, van der Luijt, Rob B, Menko, Fred H, Bart, Joost, de Vries, Elisabeth G E, van der Wall, Elsken
Format: Article
Language:English
Subjects:
Adult
Aged
Angiogenesis
Biology
BRCA1 protein
BRCA1 Protein - genetics
BRCA1 Protein - metabolism
BRCA2 protein
BRCA2 Protein - genetics
BRCA2 Protein - metabolism
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer
Carcinogenesis
Carcinogens
Carcinoma
Carcinoma, Intraductal, Noninfiltrating - genetics
Carcinoma, Intraductal, Noninfiltrating - metabolism
Carcinoma, Intraductal, Noninfiltrating - pathology
Carriers
Development and progression
Female
Gangrene
Gene Expression Regulation, Neoplastic
Gene mutations
Genetic aspects
Genetics
Germ-Line Mutation
Heterozygote
Histopathology
Human subjects
Humans
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Immunohistochemistry
Internal medicine
Invasiveness
Lesions
Mammography
Markers
Medical research
Medicine
Medicine, Experimental
Middle Aged
Mutation
Neoplasm Grading
Neoplasm Invasiveness
Pathology
Patients
Proteins
Therapy
Tumors
Vascular endothelial growth factor
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0056055