The RUNX transcriptional coregulator, CBFB, suppresses migration of ERþ breast cancer cells by repressing ERA-mediated expression of the migratory factor TFF1

Abstract

Core binding factor b (CBFb), the essential coregulator of RUNX transcription factors, is one of the most frequently mutated genes in estrogen receptor–positive (ERþ) breast cancer. Many of these mutations are nonsense mutations and are predicted to result in loss of function, suggesting a tumor suppressor role for CBFb. However, the impact of missense mutations and the loss of CBFb in ERþ breast cancer cells have not been determined. Here we demonstrate that missense mutations in CBFb accumulate near the Runt domain–binding region. These mutations inhibit the ability of CBFb to form CBFb–Runx–DNA complexes. We further show that deletion of CBFb, using CRISPR-Cas9, in ERþ MCF7 cells results in an increase in cell migration. This increase in migration is dependent on the presence of ERa. Analysis of the potential mechanism revealed that the increase in migration is driven by the coregulation of Trefoil factor 1 (TFF1) by CBFb and ERa. RUNX1–CBFb acts to repress ERa-activated expression of TFF1. TFF1 is a motogen that stimulates migration and we show that knockdown of TFF1 in CBFb/ cells inhibits the migratory phenotype. Our findings reveal a new mechanism by which RUNX1–CBFb and ERa combine to regulate gene expression and a new role for RUNX1–CBFb in the prevention of cell migration by suppressing the expression of the motogen TFF1. Implications: Mutations in CBFb contribute to the development of breast cancer by inducing a metastatic phenotype that is dependent on ER.