title: 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.
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors: D
authors: D
authors: Tkocz
authors: N T
authors: NT
authors: Crawford
authors: N E
authors: NE
authors: Buckley
authors: F B
authors: FB
authors: Berry
authors: R D
authors: RD
authors: Kennedy
authors: J J
authors: JJ
authors: Gorski
authors: D P
authors: DP
authors: Harkin
authors: P B
authors: PB
authors: Mullan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D019313:BRCA1 Protein / Q000502:physiology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015251:Epirubicin / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D020128:Inhibitory Concentration 50; D016685:Mitomycin / Q000494:pharmacology; D008969:Molecular Sequence Data; D018295:Neoplasms, Basal Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D015251:Epirubicin; D016685:Mitomycin; D005472:Fluorouracil