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Oncogene
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Oncogene
Article . 2011 . Peer-reviewed
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BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

Authors: Tkocz, D.; Crawford, Nyree; Buckley, Niamh E; Berry, F.B.; Kennedy, Richard; Miskelly, Julia; Harkin, Paul; +1 Authors

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

Abstract

In this study we describe a novel interaction between the breast/ovarian tumor suppressor gene BRCA1 and the transcription factor GATA3, an interaction, which is important for normal breast differentiation. We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that FOXC1 is an essential survival factor maintaining the proliferation of BLBCs cell lines. We define the mechanistic basis of this corepression and identify the GATA3-binding site within the FOXC1 distal promoter region. We show that BRCA1 and GATA3 interact on the FOXC1 promoter and that BRCA1 requires GATA3 for recruitment to this region. This interaction requires fully functional BRCA1 as a mutant BRCA1 protein is unable to localize to the FOXC1 promoter or repress FOXC1 expression. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. Finally, we demonstrate the importance of our findings by showing that loss of GATA3 expression or aberrant FOXC1 expression contributes to the drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs.

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Keywords

/dk/atira/pure/subjectarea/asjc/1300/1311, Epithelial-Mesenchymal Transition, /dk/atira/pure/subjectarea/asjc/1300/1312, name=Genetics, Mitomycin, Molecular Sequence Data, 610, name=Cancer Research, Antineoplastic Agents, Breast Neoplasms, GATA3 Transcription Factor, Inhibitory Concentration 50, Cell Line, Tumor, Humans, Cell Proliferation, Epirubicin, Base Sequence, BRCA1 Protein, Forkhead Transcription Factors, name=Molecular Biology, name=SDG 3 - Good Health and Well-being, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Gene Knockdown Techniques, /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, Female, Fluorouracil, /dk/atira/pure/subjectarea/asjc/1300/1306

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    selected citations
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    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    86
    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Top 10%
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 10%
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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
86
Top 10%
Top 10%
Top 10%
bronze