Mutations in the BRCA1 gene predispose carriers to breast and ovarian cancer, but are also associated with sporadic cancers of other organs. BRCA1, as heterodimer with its protein binding partner BARD1, has tumor suppressor functions in DNA repair and cell cycle control, due to the ubiquitin ligase activity of the BRCA1-BARD1 complex. While formation of the BRCA1-BARD1 heterodimer depends on the N-terminal RING fingers of both proteins, the C-terminus of the BARD1 has also a function in mitosis. Interestingly, cancer cells express BARD1 isoforms that lack the RING finger and repress full length (FL) BARD1. SiRNA depletion of isoforms in cancer cells deficient of FL BARD1 leads to growth arrest in vitro. Furthermore, an N-terminally truncated isoform, but not FL BARD1, can bind to the mitotic kinase Aurora B, which is often upregulated in cancer. We investigated the role of BARD1 isoforms in NSCLC. Immunohistochemistry and RT-PCR, performed on biopsies, showed loss of BARD1 N-terminal epitopes and exons, respectively. Since the C-terminus of BARD1 is involved in pro-proliferative functions through binding to Aurora B, we investigated whether expression of BARD1 isoforms was correlated with Aurora B expression in NSCLC. Co-expression of Aurora B and BARD1 isoforms was found in bronchoalveolar carcinoma. Our data demonstrate that truncated BARD1 isoforms that are deficient of BRCA1-linked tumor suppressor functions are expressed in NSCLC. Since BARD1 isoforms can interact with Aurora B in vitro, the co-expression of truncated BARD1 and Aurora B in NSCLC suggests that they act in a common oncogenic pathway.

Truncated isoforms of BRCA1-associated protein BARD1 are expressed in NSCLC and are potential targets for treatment

BIANCO, Andrea
2009

Abstract

Mutations in the BRCA1 gene predispose carriers to breast and ovarian cancer, but are also associated with sporadic cancers of other organs. BRCA1, as heterodimer with its protein binding partner BARD1, has tumor suppressor functions in DNA repair and cell cycle control, due to the ubiquitin ligase activity of the BRCA1-BARD1 complex. While formation of the BRCA1-BARD1 heterodimer depends on the N-terminal RING fingers of both proteins, the C-terminus of the BARD1 has also a function in mitosis. Interestingly, cancer cells express BARD1 isoforms that lack the RING finger and repress full length (FL) BARD1. SiRNA depletion of isoforms in cancer cells deficient of FL BARD1 leads to growth arrest in vitro. Furthermore, an N-terminally truncated isoform, but not FL BARD1, can bind to the mitotic kinase Aurora B, which is often upregulated in cancer. We investigated the role of BARD1 isoforms in NSCLC. Immunohistochemistry and RT-PCR, performed on biopsies, showed loss of BARD1 N-terminal epitopes and exons, respectively. Since the C-terminus of BARD1 is involved in pro-proliferative functions through binding to Aurora B, we investigated whether expression of BARD1 isoforms was correlated with Aurora B expression in NSCLC. Co-expression of Aurora B and BARD1 isoforms was found in bronchoalveolar carcinoma. Our data demonstrate that truncated BARD1 isoforms that are deficient of BRCA1-linked tumor suppressor functions are expressed in NSCLC. Since BARD1 isoforms can interact with Aurora B in vitro, the co-expression of truncated BARD1 and Aurora B in NSCLC suggests that they act in a common oncogenic pathway.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11591/329266
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