TLE3 Sustains Luminal Breast Cancer Lineage Fidelity to Suppress Metastasis

Breast cancer subtypes and their phenotypes parallel different stages of the mammary epithelial cell developmental hierarchy. Discovering mechanisms that control lineage identity could provide novel avenues for mitigating disease progression. Here we report that the transcriptional corepressor TLE3 is a guardian of luminal cell fate in breast cancer and operates independently of the estrogen receptor. In luminal breast cancer, TLE3 actively repressed the gene-expression signature associated with highly aggressive basal-like breast cancers (BLBC). Moreover, mainte-nance of the luminal lineage depended on the appropriate localization of TLE3 to its transcriptional targets, a process mediated by interactions with FOXA1. By repressing genes that drive BLBC phenotypes, including SOX9 and TGFb2, TLE3 prevented the acquisition of a hybrid epithelial-mesenchymal state and reduced metastatic capacity and aggressive cellular behaviors. These results establish TLE3 as an essential tran-scriptional repressor that sustains the more differentiated and less metastatic nature of luminal breast cancers. Approaches to induce TLE3 expression could promote the acquisition of less aggressive, more treatable disease states to extend patient survival.

Automated summary

Breast cancer subtypes and their phenotypes correspond to different stages of mammary epithelial cell development. The discovery of mechanisms that control lineage identity may offer new opportunities for reducing disease progression. This study reveals that the transcriptional corepressor TLE3 functions as a guardian of luminal cell fate in breast cancer, independent of the estrogen receptor. TLE3 represses the gene-expression signature associated with aggressive basal-like breast cancers, thereby reducing metastatic capacity and aggressive behaviors.