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Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas

Nature Genetics volume 21, pages 236–240 (1999)Cite this article

Abstract

Although the link between the BRCA1 tumour–suppressor gene and hereditary breast and ovarian cancer is established1,2,3,4,5, the role, if any, of BRCA1 in non–familial cancers is unclear. BRCA1 mutations are rare in sporadic cancers6,7,8, but loss of BRCA1 resulting from reduced expression or incorrect subcellular localization9,10 is postulated to be important in non–familial breast and ovarian cancers. Epigenetic loss, however, has not received general acceptance due to controversy regarding the subcellular localization of BRCA1 proteins, reports of which have ranged from exclusively nuclear11,12,13,14,15, to conditionally nuclear10, to the ER/golgi16, to cytoplasmic invaginations into the nucleus17. In an attempt to resolve this issue, we have comprehensively characterized 19 anti–BRCA1 antibodies. These reagents detect a 220–kD protein localized in discrete nuclear foci in all epithelial cell lines, including those derived from breast malignancies. Immunohistochemical staining of human breast specimens also revealed BRCA1 nuclear foci in benign breast, invasive lobular cancers and low–grade ductal carcinomas. Conversely, BRCA1 expression was reduced or undetectable in the majority of high–grade, ductal carcinomas, suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers.

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Figure 1: Identification of endogenous BRCA1.
Figure 2: Identification of BRCA1 nuclear dots.
Figure 3: Nuclear BRCA1 staining in breast and ovarian tissues.
Figure 4: IHC controls for BRCA1 staining in breast and ovarian tissues.

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Acknowledgements

We thank H. Ruffner, I. Verma, W.–H. Lee and D. Hill for kindly supplying BRCA1 antibodies. We would also like to thank A. Lopez for assistance with the statistical analysis. This work was supported by grants from the U.S. Army Breast Cancer Research Program (DAMD17–94–J–4118 and DAMD17–94–J–4234) and by NIH grant RO1 CA36827 as well as by funds from the Revlon/UCLA Women's Cancer Research Program (R/U WCRP). C.A.W. is a postdoctoral fellow of the R/U WCRP and is supported by a Bank of America/Giannini Foundation Fellowship.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology–Oncology, UCLA School of Medicine, Los Angeles, 90095, California, USA

    Cindy A. Wilson, Lillian Ramos, Maria R. Villaseñor, Kathy Clarke, Beth Karlan & Dennis J. Slamon

  2. Department of Pathology, Southern California Permanente Medical Group, 5601 De Soto Ave, Woodland Hills , 91365, California, USA

    Karl H. Anders, Robert H. Zuch, Michael H. Kanter & Sylvan Cohen

  3. Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave , Los Angeles, 90033, California, USA

    Michael F. Press

  4. Charles A. Dana Division of Human Cancer Genetics, Dana–Farber Cancer Institute, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Jun-Jie Chen, Ralph Scully & David Livingston

  5. Molecular Biology, Amgen Inc., Amgen Center, Thousand Oaks, 91320, California, USA

    Frank J. Calzone

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  1. Cindy A. Wilson
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Correspondence to Dennis J. Slamon.

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Wilson, C., Ramos, L., Villaseñor, M. et al. Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nat Genet 21, 236–240 (1999). https://doi.org/10.1038/6029

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