ESR1mutant breast cancers show elevated basal cytokeratins and immune activation

Author:

Li ZheqiORCID,Wu Yang,Bahreini Amir,Priedigkeit Nolan M.,Ding Kai,Sartorius Carol A.,Miller Lori,Rosenzweig Margaret,Wagle Nikhil,Richer Jennifer K.,Muller William J.,Buluwela Laki,Ali Simak,Fang Yusi,Zhu Li,Tseng George C.ORCID,Gertz Jason,Atkinson Jennifer M.,Lee Adrian V.ORCID,Oesterreich Steffi

Abstract

AbstractEstrogen receptor alpha (ER/ESR1) is mutated in 30-40% of endocrine resistant ER-positive (ER+) breast cancer.ESR1mutations cause ligand-independent growth and increased metastasisin vivoandin vitro. Despite the distinct clinical features and changes in therapeutic response associated withESR1mutations, there are no data about their potential role in intrinsic subtype switching. Applying four luminal and basal gene set pairs,ESR1mutant cell models and clinical samples showed a significant enrichment of basal subtype markers. Among them, the six basal cytokeratins (BCKs) were the most enriched genes. Induction of BCKs was independent of ER binding and instead associated with chromatin reprogramming centered around a progesterone receptor-orchestrated topological associated domain at theKRT14/16/17genomic region. Unexpectedly, highBCKexpression in ER+ primary breast cancer is associated with good prognosis, and these tumors show enriched activation of a number of immune pathways, a distinctive feature shared withESR1mutant tumors. S100A8 and S100A9 were among the most highly induced immune mediators shared between high-BCKs ER+ andESR1mutant tumors, and single-cell RNA-seq analysis inferred their involvement in paracrine crosstalk between epithelial and stromal cells. Collectively, these observations demonstrate thatESR1mutant tumors gain basal features with induction of basal cytokeratins via epigenetic mechanisms in rare subpopulation of cells. This is associated with increased immune activation, encouraging additional studies of immune therapeutic vulnerabilities inESR1mutant tumors.

Publisher

Cold Spring Harbor Laboratory

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