ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation

Author:

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

Abstract

AbstractEstrogen 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.

Funder

U.S. Department of Health & Human Services | NIH | National Cancer Institute

U.S. Department of Defense

Publisher

Springer Science and Business Media LLC

Subject

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

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