TLE3 Sustains Luminal Breast Cancer Lineage Fidelity to Suppress Metastasis

Lindsey J. Anstine, Parth R. Majmudar, Amy Aponte, Salendra Singh, Ran Zhao, Kristen L. Weber-Bonk, Fadi W. Abdul-Karim, Mitchell Valentine, Darcie D. Seachrist, Katelyn E. Grennel-Nickelson, Leslie Cuellar-Vite, Gina M. Sizemore, Steven T. Sizemore, Bryan M. Webb, Cheryl L. Thompson, Ruth A. Keri

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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, maintenance 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 transcriptional 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 Significance: Transcriptional corepressor TLE3 actively suppresses SOX9 and TGFb transcriptional programs to sustain the luminal lineage identity of breast cancer cells and to inhibit metastatic progression.(Figure Presented).

Original languageEnglish (US)
Pages (from-to)997-1015
Number of pages19
JournalCancer Research
Volume83
Issue number7
DOIs
StatePublished - Apr 1 2023

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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