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.

The Forkhead Box Transcription Factor FOXC1 Promotes Breast Cancer Invasion by Inducing Matrix Metalloprotease 7 (MMP7) Expression

“…Silencing of FOXC1 has previously been shown to decrease viability or proliferation in a number of cell types (29,30). In agreement with these previous findings, FOXC1 silencing in basal A breast cancer cell lines resulted in a substantial decrease in cell number compared with control treated cells (data not shown).…”

“…Basal A cell lines are most like BLBC, whereas basal B lines are more similar to the rare claudin-low breast cancer subtype. Of note, there are several conflicting reports regarding the relative expression level of the FOXC1 protein in breast cancer cell lines (15,17,29). To exclude the possibility that the data presented herein was associated with poor antibody specificity, these data were confirmed using additional antibodies to FOXC1 and MMP7 (supplemental Fig.…”

An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response in MCF-7 breast cancer cells

“…This analysis confirms previous findings that FOXC1 and GATA3 are involved in a switch (Supplemental Fig. S2D) between basal-like and luminal-like expression programs in breast cancer (Tkocz et al 2011), and indicates that the high-resolution time-series data may identify novel factors that underlie this switch.…”

“…These data have provided a wealth of insight into the dynamics of the estrogen response. We observe similar temporal responses for genes that encode the transcription factors previously reported to be involved in positive feedback loops (ERα and GATA3; Eeckhoute et al 2007) and opposite temporal responses for genes encoding transcription factors reported to inhibit each other (GATA3 and FOXC1; Tkocz et al 2011). These temporal relationships allow us to make inferences about the estrogen-stimulated regulatory network and enhance our understanding of the timing of the cascade of signaling stimulated by estrogen in breast cancer.…”

GATA3 (GATA binding protein 3)

“…Moreover, Gata3 interact with BRCA1 to repress the expression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including Foxc1, Foxc2, Cxcl1 and P-cadherin. Loss of GATA3 expression also contributes to drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs (Tkocz et al, 2011). In T cells, Gata3 acts at multiple stages of thymocyte differentiation.…”