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 Fang, Li Zhu, George C. Tseng, Jason Gertz, Jennifer M. Atkinson, Adrian V. Lee and Steffi Oesterreich ()
Additional contact information
Zheqi Li: University of Pittsburgh
Olivia McGinn: UPMC Hillman Cancer Center
Yang Wu: UPMC Hillman Cancer Center
Amir Bahreini: UPMC Hillman Cancer Center
Nolan M. Priedigkeit: University of Pittsburgh
Kai Ding: UPMC Hillman Cancer Center
Sayali Onkar: UPMC Hillman Cancer Center
Caleb Lampenfeld: University of Pittsburgh
Carol A. Sartorius: University of Colorado Anschutz Medical Campus
Lori Miller: UPMC Hillman Cancer Center
Margaret Rosenzweig: University of Pittsburgh
Ofir Cohen: Dana-Farber Cancer Institute, Harvard Medical School
Nikhil Wagle: Dana-Farber Cancer Institute, Harvard Medical School
Jennifer K. Richer: University of Colorado Anschutz Medical Campus
William J. Muller: McGill University
Laki Buluwela: Hammersmith Hospital Campus
Simak Ali: Hammersmith Hospital Campus
Tullia C. Bruno: University of Pittsburgh
Dario A. A. Vignali: University of Pittsburgh
Yusi Fang: University of Pittsburgh
Li Zhu: University of Pittsburgh
George C. Tseng: University of Pittsburgh
Jason Gertz: University of Utah
Jennifer M. Atkinson: University of Pittsburgh
Adrian V. Lee: University of Pittsburgh
Steffi Oesterreich: University of Pittsburgh

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29498-9

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