Dysfunction of the Reciprocal Feedback Loop between GATA3- and ZEB2-Nucleated Repression Programs Contributes to Breast Cancer Metastasis

How loss-of-function of GATA3 contributes to the development of breast cancer is poorly understood. Here, we report that GATA3 nucleates a transcription repression program composed of G9A and MTA3-, but not MTA1- or MTA2-, constituted NuRD complex. Genome-wide analysis of the GATA3/G9A/NuRD(MTA3) targets identified a cohort of genes including ZEB2 that are critically involved in epithelial-to-mesenchymal transition and cell invasion. We demonstrate that the GATA3/G9A/NuRD(MTA3) complex inhibits the invasive potential of breast cancer cells in vitro and suppresses breast cancer metastasis in vivo. Strikingly, the expression of GATA3, G9A, and MTA3 is concurrently downregulated during breast cancer progression, leading to an elevated expression of ZEB2, which, in turn, represses the expression of G9A and MTA3 through the recruitment of G9A/NuRD(MTA1). •GATA3 is physically associated with the G9A/NuRD(MTA3) complex•The GATA3/G9A/NuRD(MTA3) complex represses ZEB2•The GATA3/G9A/NuRD(MTA3) complex suppresses the metastasis of breast cancer•The ZEB2/G9A/NuRD(MTA1) complex represses G9A and MTA3 Si et al. show that GATA3 interacts with G9A and the NuRD (MTA3) complex to transcriptionally repress genes involved in epithelial-to-mesenchymal transition. Dysfunctional reciprocal feedback regulation between GATA3/G9A/NuRD(MTA3) and ZEB2/G9A/NuRD(MTA1) contributes to breast cancer progression.