Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer.
Male breast cancer is poorly understood with a large proportion arising in the familial context particularly with the BRCA2 germline mutation. As phenotypic and genotypic differences between sporadic and familial male breast cancers have been noted, we investigated the importance of a hypoxic drive in these cancers as this pathway has been shown to be of importance in familial female breast cancer. Expression of two major hypoxia-induced proteins, the hypoxia-inducible factor-1α (HIF1A) and the carbonic anhydrase IX (CA9), examined within a large cohort including 61 familial (3 BRCA1, 28 BRCA2, 30 BRCAX) and 225 sporadic male breast cancers showed that 31% of all male breast cancers expressed either HIF1A (25%) and/or CA9 (8%) in the combined cohort. Expression of HIF1A correlated with an increased incidence of a second-major malignancy (P=0.04), histological tumor type (P=0.005) and basal phenotype (P=0.02). Expression of CA9 correlated with age (P=0.004) in sporadic cases and an increased tumor size (P=0.003). Expression of HIF1A was prognostic for disease-specific survival in sporadic male breast cancers (HR: 3.8, 95% CI: 1.5-9.8, P=0.006) but not within familial male breast cancer, whereas CA9 was only prognostic in familial male breast cancers (HR: 358.0, 95% CI: 9.3-13781.7, P=0.002) and not in sporadic male breast cancer. This study found that hypoxic drive is less prevalent in male breast cancer compared with female breast cancer, possibly due to a different breast microenvironment. The prognostic impact of HIF1A is greatest in sporadic male breast cancers with an alternate dominant mechanism for the oncogenic drivers suggested in high risk familial male breast cancers.
1] Department of Pathology, Peter MacCallum Cancer Center, Melbourne, Australia [2] Department of Pathology and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
Siddhartha
S
Deb
Department of Oncology, Clinical Sciences and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
Ida
I
Johansson
Department of Pathology, Peter MacCallum Cancer Center, Melbourne, Australia.
David
D
Byrne
Center for Clinical Research, Central Hospital of Västerås, Västerås, Sweden.
Cecilia
C
Nilsson
Kathleen Cunningham Foundation Consortium for research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia.
Melbourne Pathology, Melbourne, Australia.
Leonie
L
Constable
Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden.
Marie-Louise
ML
Fjällskog
1] Department of Pathology, Peter MacCallum Cancer Center, Melbourne, Australia [2] Department of Pathology and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
Alexander
A
Dobrovic
Department of Oncology, Clinical Sciences and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
Ingrid
I
Hedenfalk
1] Department of Pathology, Peter MacCallum Cancer Center, Melbourne, Australia [2] Department of Pathology and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
Stephen B
SB
Fox
D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics; D019313:BRCA1 Protein / Q000378:metabolism; D024682:BRCA2 Protein / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D011379:Prognosis; D046888:Tissue Array Analysis
D000951:Antigens, Neoplasm; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases