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BRCA1 transcriptionally regulates genes associated with the basal-like phenotype in breast cancer

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Abstract

Expression profiling of BRCA1-deficient tumours has identified a pattern of gene expression similar to basal-like breast tumours. In this study, we examine whether a BRCA1-dependent transcriptional mechanism may underpin the link between BRCA1 and basal-like phenotype. In methods section, the mRNA and protein were harvested from a number of BRCA1 mutant and wild-type breast cancer cell lines and from matched isogenic controls. Microarray-based expression profiling was used to identify potential BRCA1-regulated transcripts. These gene targets were then validated (by in silico analysis of tumour samples) by real-time PCR and Western blot analysis. Chromatin immunoprecipitation (ChIP) assays were used to confirm recruitment of BRCA1 to specific promoters. In results, we demonstrate that functional BRCA1 represses the expression of cytokeratins 5(KRT5) and 17(KRT17) and p-Cadherin (CDH3) in HCC1937 and T47D breast cancer cell lines at both mRNA and protein level. ChIP assays demonstrate that BRCA1 is recruited to the promoters of KRT5, KRT17 and CDH3, and re-ChIP assays confirm that BRCA1 is recruited independently to form c-Myc and Sp1 complexes on the CDH3 promoter. We show that siRNA-mediated inhibition of endogenous c-Myc (and not Sp1) results in a marked increase in CDH3 expression analogous to that observed following the inhibition of endogenous BRCA1. The data provided suggest a model whereby BRCA1 and c-Myc form a repressor complex on the promoters of specific basal genes and represent a potential mechanism to explain the observed overexpression of key basal markers in BRCA1-deficient tumours.

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Authors and Affiliations

  1. Department of Oncology, Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, BT9 7BL, N. Ireland, UK

    Julia J. Gorski, Colin R. James, Jennifer E. Quinn, Gail E. Stewart, Kieran Crosbie Staunton, Niamh E. Buckley, Richard H. Wilson, Paul B. Mullan & D. Paul Harkin

  2. Almac Diagnostics, Seagoe Industrial Estate, Craigavon, BT63 5QD, UK

    Fionnuala A. McDyer & Richard D. Kennedy

Authors
  1. Julia J. Gorski
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  2. Colin R. James
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  3. Jennifer E. Quinn
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  4. Gail E. Stewart
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  5. Kieran Crosbie Staunton
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  6. Niamh E. Buckley
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  7. Fionnuala A. McDyer
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  8. Richard D. Kennedy
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  9. Richard H. Wilson
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  10. Paul B. Mullan
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  11. D. Paul Harkin
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Corresponding author

Correspondence to Julia J. Gorski.

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Funding bodies

Julia Gorski and Niamh Buckley: R&D Office NI, Colin James: Cancer Research UK, Jennifer Quinn: Breast Cancer Campaign, Gail Stewart: Medical Research Council, Kieran Crosbie Staunton: European Social Fund, Richard Wilson: Queens University Belfast, Richard Kennedy and Fionnuala McDyer: Almac Diagnostics, Paul Mullan: Action Cancer N. I., Paul Harkin: Breast Cancer Campaign and Cancer Research UK.

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Gorski, J.J., James, C.R., Quinn, J.E. et al. BRCA1 transcriptionally regulates genes associated with the basal-like phenotype in breast cancer. Breast Cancer Res Treat 122, 721–731 (2010). https://doi.org/10.1007/s10549-009-0565-0

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  • DOI: https://doi.org/10.1007/s10549-009-0565-0

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