Summary
Accumulating genetic and biochemical evidences support a role for the SWI/SNF chromatin-remodeling complex in cancer development and multiple core subunits of these complexes have been found to function as tumor suppressor genes. The core SWI/SNF subunit BAF57 mediates direct interactions with estrogen and androgen receptors (ER and AR) regulating their transcriptional activity. BAF57 gene maps to chromosome band 17 q21 in close proximity to the BRCA1 gene. This locus has been associated with frequent loss of heterozygosity (LOH) and allelic imbalance in breast cancers; however, BRCA1 mutations are rare events in sporadic breast cancer with LOH in the region, suggesting that another tumor suppressor gene resides in this area. All these reasons prompted us to screen for mutations in the BAF57 gene using a panel of the most commonly used human breast cancer cell lines. All cell lines analysed contain wild-type copies of BAF57 gene with the only exception of the breast ductal carcinoma cell line BT549. Sequencing of genomic DNA and cDNA generated from BT549 mRNA demonstrated the presence of a CA dinucleotide insertion in exon 5 of BAF57. The absence of wild-type BAF57 alleles indicates that this is a biallelic inactivating mutation that causes a frameshift and as a consequence a premature stop codon leading to a truncated BAF57 protein. A functional characterisation of the truncated BAF57 showed that it has lost the ability to bind to ER but still binds to the nuclear receptor coactivator SRC1e. Furthermore, we observed that the expression of the truncated BAF57 increased the ability of SRC1e to potentiate transcriptional activation by ERα, suggesting that mutations in BAF57 could contribute to the oncogenic transformation in breast cancer cells.
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Acknowledgements
We are grateful to Roman Mullenbach for his help in setting up the genomic sequencing assay. Our work was funded by the Wellcome Trust (grant 061930), the Association for International Cancer Research (03-098) and Ministerio de Educación y Ciencia (SAF2004-02549).
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Kiskinis, E., García-Pedrero, J.M., Villaronga, M.A. et al. Identification of BAF57 mutations in human breast cancer cell lines. Breast Cancer Res Treat 98, 191–198 (2006). https://doi.org/10.1007/s10549-005-9149-9
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DOI: https://doi.org/10.1007/s10549-005-9149-9