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Oncogenic BARD1 Isoforms Expressed in Gynecological Cancers

¹ Laboratory of Molecular Gynecology and Obstetrics, Department of Gynecology and Obstetrics and Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland; ² Laboratory of Molecular Genetics, Department of Internal Medicine 1, Medical University of Vienna; ³ Molecular Oncology Group, Medical University of Vienna, Vienna, Austria; and ⁴ Institute of Experimental Oncology, Bellinzona, Switzerland

Requests for reprints: Irmgard Irminger-Finger, Laboratory of Molecular Gynecology and Obstetrics, Department of Gynecology and Obstetrics, Geneva University Hospitals, Maternité 30, Bld de la Cluse, CH-1211, Geneva, Switzerland. Phone: 41-22-382-43-27; Fax: 41-22-382-41-45; E-mail: Irmgard.irminger{at}hcuge.ch.

BARD1 is required for protein stability and tumor suppressor functions of BRCA1, which depend on the ubiquitin ligase activity of the BRCA1-BARD1 heterodimer. The NH₂-terminal RING domains of both proteins act as interaction modules and form a ubiquitin ligase, which has functions in DNA repair, cell cycle checkpoint regulation, and mitosis. Interestingly, up-regulated expression of truncated BARD1 isoforms was found to be associated with poor prognosis in breast and ovarian cancers and, in a hormonally regulated fashion, in the human cytotrophoblast, a cell type with properties reminiscent of cancer cells. We therefore performed reverse transcription-PCR to determine the structure of BARD1 isoforms in cell lines derived from hormone-dependent and hormone-independent cancers. We found a specific combination of isoforms, generated by differential splicing and alternative transcription initiation, mostly lacking the BRCA1 interaction domain, in gynecologic but not hematologic cancer cell lines. To investigate the prevalence of BARD1 isoforms in tumors, we applied immunohistochemistry to ovarian cancers, using antibodies distinguishing full-length BARD1 and isoforms. Expression of NH₂ terminally truncated BARD1 was correlated with advanced stage of cancer, and expression of spliced isoforms was typical for clear cell carcinoma, the ovarian cancer with worst prognosis, suggesting a role of BARD1 isoforms in cancer progression. To challenge this hypothesis, we silenced BARD1 isoforms in ovarian cancer cells that lacked wild-type BARD1 by siRNA interference, which led to a complete proliferation arrest. Thus, BARD1 isoform expression is required for cancer cell proliferation, which is compatible with the notion that BARD1 isoforms act as cancer maintenance genes. [Cancer Res 2007;67(24):11876–85]

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				Correction: BARD1 Isoforms in Cancer Cancer Res., February 15, 2008; 68(4): 1245 - 1245. [Full Text] [PDF]