The RUNX Transcriptional Coregulator, CBF beta, Suppresses Migration of ER+ Breast Cancer Cells by Repressing ER alpha-Mediated Expression of the Migratory Factor TFF1

摘要

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