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

Abstract

Core binding factor β (CBFβ), 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 CBFβ. However, the impact of missense mutations and the loss of CBFβ in ER+ breast cancer cells have not been determined. Here we demonstrate that missense mutations in CBFβ accumulate near the Runt domain-binding region. These mutations inhibit the ability of CBFβ to form CBFβ-Runx-DNA complexes. We further show that deletion of CBFβ, using CRISPR-Cas9, in ER+ MCF7 cells results in an increase in cell migration. This increase in migration is dependent on the presence of ERα. Analysis of the potential mechanism revealed that the increase in migration is driven by the coregulation of Trefoil factor 1 (TFF1) by CBFβ and ERα. RUNX1-CBFβ acts to repress ERα-activated expression of TFF1. TFF1 is a motogen that stimulates migration and we show that knockdown of TFF1 in CBFβ-/- cells inhibits the migratory phenotype. Our findings reveal a new mechanism by which RUNX1-CBFβ and ERα combine to regulate gene expression and a new role for RUNX1-CBFβ in the prevention of cell migration by suppressing the expression of the motogen TFF1. IMPLICATIONS: Mutations in CBFβ contribute to the development of breast cancer by inducing a metastatic phenotype that is dependent on ER.