ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation

Zheqi Li, Olivia McGinn, Yang Wu, Amir Bahreini, Nolan M. Priedigkeit, Kai Ding, Sayali Onkar, Caleb Lampenfeld, Carol A. Sartorius, Lori Miller, Margaret Rosenzweig, Ofir Cohen, Nikhil Wagle, Jennifer K. Richer, William J. Muller, Laki Buluwela, Simak Ali, Tullia C. Bruno, Dario A.A. Vignali, Yusi FangLi Zhu, George C. Tseng, Jason Gertz, Jennifer M. Atkinson, Adrian V. Lee, Steffi Oesterreich

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Estrogen receptor alpha (ER/ESR1) is frequently mutated in endocrine resistant ER-positive (ER+) breast cancer and linked to ligand-independent growth and metastasis. Despite the distinct clinical features of ESR1 mutations, their role in intrinsic subtype switching remains largely unknown. Here we find that ESR1 mutant cells and clinical samples show a significant enrichment of basal subtype markers, and six basal cytokeratins (BCKs) are the most enriched genes. Induction of BCKs is independent of ER binding and instead associated with chromatin reprogramming centered around a progesterone receptor-orchestrated insulated neighborhood. BCK-high ER+ primary breast tumors exhibit a number of enriched immune pathways, shared with ESR1 mutant tumors. S100A8 and S100A9 are among the most induced immune mediators and involve in tumor-stroma paracrine crosstalk inferred by single-cell RNA-seq from metastatic tumors. Collectively, these observations demonstrate that ESR1 mutant tumors gain basal features associated with increased immune activation, encouraging additional studies of immune therapeutic vulnerabilities.

Original languageEnglish
Article number2011
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - 1 Dec 2022
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General
  • General Physics and Astronomy

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