TY - JOUR
T1 - ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation
AU - Li, Zheqi
AU - McGinn, Olivia
AU - Wu, Yang
AU - Bahreini, Amir
AU - Priedigkeit, Nolan M.
AU - Ding, Kai
AU - Onkar, Sayali
AU - Lampenfeld, Caleb
AU - Sartorius, Carol A.
AU - Miller, Lori
AU - Rosenzweig, Margaret
AU - Cohen, Ofir
AU - Wagle, Nikhil
AU - Richer, Jennifer K.
AU - Muller, William J.
AU - Buluwela, Laki
AU - Ali, Simak
AU - Bruno, Tullia C.
AU - Vignali, Dario A.A.
AU - Fang, Yusi
AU - Zhu, Li
AU - Tseng, George C.
AU - Gertz, Jason
AU - Atkinson, Jennifer M.
AU - Lee, Adrian V.
AU - Oesterreich, Steffi
N1 - Funding Information:
We thank Dr. Peilu Wang for her contribution to earlier ESR1 mutant-studies in the Lee-Oesterreich group. We thank Corrine Farrell, Jian Chen, Dr. Jagmohan Hooda, Christy Smolak and Dr. Peter Lucas for some technical support of the project. We also thank Dr. Alana Welm from University of Utah for providing the HCI-013EI PDX model. This project used the University of Pittsburgh Pitt Biospecimen Core (PBC), Cytometry Facility, and Tissue and Research Pathology Service (TARPS) supported in part by award NIH grant P30CA047904. The authors would like to thank the patients who contributed samples to the tissue bank as well as all the clinicians and staff for their efforts in collecting tissues. This work was supported by a Susan G. Komen Scholar awards [SAC110021 to A.V.L.]; the National Cancer Institute [R01CA221303 to S.O. (Oesterreich) and P30CA047904]; the Department of Defense [W81XWH1910499 to S.O. (Oesterreich); DOD grant W81XWH1910434 (J.G.)]; Magee-Women’s Research Institute and Foundation, Nicole Meloche Foundation, Penguins Alumni Foundation, the Pennsylvania Breast Cancer Coalition and the Shear Family Foundation. S.O. (Oesterreich) and A.V.L. are Hillman Fellows. Z.L. is supported by John S. Lazo Cancer Pharmacology Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other Institutes and Foundations.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128432361&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-29498-9
DO - 10.1038/s41467-022-29498-9
M3 - Article
C2 - 35440136
AN - SCOPUS:85128432361
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2011
ER -