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[Cancer Research 62, 1481-1488, March 1, 2002]
© 2002 American Association for Cancer Research

Molecular Biology and Genetics

Molecular-Cytogenetic Analysis of HER-2/neu Gene in BRCA1-associated Breast Cancers1

Tatyana A. Grushko, M. Anne Blackwood, Phil L. Schumm, Fitsum G. Hagos, Moses O. Adeyanju, Michael D. Feldman, Melinda O. Sanders, Barbara L. Weber and Olufunmilayo I. Olopade2

Section of Hematology/Oncology, Department of Medicine, Committees on Genetics and Cancer Biology [T. A. G., F. G. H., O. I. O], and Department of Health Studies [P. L. S.], University of Chicago, Chicago, Illinois 60637-1463; Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021 [M. A. B.]; Laboratory Corporation of America, Elmhurst, Illinois 60126-1539 [M. O. A.]; Pathology & Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia Pennsylvania 19104-6021 [M. D. F., M. O. S.]; and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 9104–6160 [B. L. W.]

The BRCA1 tumor suppressor gene and the HER-2/neu oncogene are located in close proximity on the long arm of chromosome 17 (17q11–21). Absence of BRCA1 or functional overexpression of the HER-2/neu gene presumably contributes to the somatic phenotype of breast cancer in premenopausal women, characterized by unfavorable prognostic features such as high tumor grade, hormone receptor negativity, and high proliferation rate. To examine whether amplification of HER-2/neu contributes to the aggressive biology of BRCA1-associated tumors, we have performed fluorescence in situ hybridization on formalin-fixed paraffin-embedded breast tumor tissue sections from 53 BRCA1 mutation carriers and 41 randomly selected, age-matched sporadic breast cancer cases. Although BRCA1-associated and sporadic tumors were equally likely (19% versus 22%) to exhibit HER-2/neu amplification [defined as a ratio of HER-2/neu copies to chromosome 17 centromere (CEP17) copies >= 2], 6 (15%) of the sporadic tumors were highly amplified (defined as a ratio >= 5) versus none of the BRCA1-associated tumors (P = 0.048). HER-2 protein overexpression as measured by immunohistochemical analysis was not observed among the BRCA1-associated cases (P = 0.042). Four of 21 (19%) sporadic tumors exhibited strong membranous staining of HER-2 (intensity level of 3+) as compared with 0 of 39 BRCA1-associated tumors. Our data suggest that a germ-line mutation in the BRCA1 tumor suppressor gene is associated with a significantly lower level of HER-2/neu amplification. Thus, it is possible that BRCA1-associated and HER-2/neu-highly amplified tumors progress through distinct molecular pathways, and the aggressive pathological features of BRCA1-associated tumors appear unrelated to amplification of the adjacent HER-2/neu oncogene.




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Copyright © 2002 by the American Association for Cancer Research.