TLE3 drives luminal identity of breast cancer through transcriptional repression of FOXA1-target genes

The identification of mechanisms controlling breast tumor progression from less aggressive to highly metastatic disease should provide novel therapeutic targets for patients. Here we report the transcriptional corepressor, TLE3, as a critical regulator of cellular plasticity in breast cancer. TLE3 facilitates repression of genes associated with the highly aggressive basal-like breast cancer (BLBC) subtype within luminal cells. Additionally, maintenance of the luminal lineage is dependent on appropriate localization of TLE3 to its transcriptional targets which is mediated through interaction with FOXA1. Furthermore, the ability of TLE3 to repress BLBC transcription results in reduced metastatic capacity and aggressive cellular behaviors. Together our findings establish TLE3 as a critical transcriptional mediator of breast cancer aggressiveness, with TLE3 sustaining the more differentiated and less metastatic nature of luminal tumors through suppression of gene expression programs associated with BLBC. Overall design: To determine the TLE3-regulated transcriptome in luminal breast cancer cells, transient silencing of TLE3 was carried out using siRNAs targeting TLE3 (siTLE3), FOXA1 (siFOXA1), or a non-silencing control (siNS) in T47D, MDA-MB-453, and SKBR3 breast cancer cell lines. At 48 hours post-transfection, RNA was collected and prepared for sequencing. RNA-seq was performed on three replicates for each experimental condition.