Hotspot ESR1 Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis

Zheqi Li, Yang Wu, Megan E. Yates, Nilgun Tasdemir, Amir Bahreini, Jian Chen, Kevin M. Levine, Nolan M. Priedigkeit, Azadeh Nasrazadani, Simak Ali, Laki Buluwela, Spencer Arnesen, Jason Gertz, Jennifer K. Richer, Benjamin Troness, Dorraya El-Ashry, Qiang Zhang, Lorenzo Gerratana, Youbin Zhang, Massimo CristofanilliMaritza A. Montanez, Prithu Sundd, Callen T. Wallace, Simon C. Watkins, Caterina Fumagalli, Elena Guerini-Rocco, Li Zhu, George C. Tseng, Nikhil Wagle, Jason S. Carroll, Paul Jank, Carsten Denkert, Maria M. Karsten, Jens Uwe Blohmer, Ben H. Park, Peter C. Lucas, Jennifer M. Atkinson, Adrian V. Lee, Steffi Oesterreich*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Constitutively active estrogen receptor a (ER/ESR1) mutations have been identified in approximately one-third of ER metastatic breast cancers. Although these mutations are known as mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant but not local recurrences in five independent breast cancer cohorts. In concordance with transcriptomic profiling of ESR1-mutant tumors, genome-edited ESR1 Y537S and D538G-mutant cell models exhibited a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally conferred enhanced cell-cell contacts while decreasing cell-extracellular matrix adhesion. In vivo studies showed ESR1- mutant cells were associated with larger multicellular circulating tumor cell (CTC) clusters with increased compactness compared with ESR1 wild-type CTCs. These preclinical findings translated to clinical observations, where CTC clusters were enriched in patients with ESR1-mutated metastatic breast cancer. Conversely, contextdependent migratory phenotypes revealed cotargeting of Wnt and ER as a vulnerability in a D538G cell model. Mechanistically, mutant ESR1 exhibited noncanonical regulation of several metastatic pathways, including secondary transcriptional regulation and de novo FOXA1-driven chromatin remodeling. Collectively, these data provide evidence for ESR1 mutation-modulated metastasis and suggest future therapeutic strategies for targeting ESR1-mutant breast cancer.

Original languageEnglish (US)
Pages (from-to)1321-1339
Number of pages19
JournalCancer Research
Volume82
Issue number7
DOIs
StatePublished - Apr 1 2022

Funding

This work was supported by the Breast Cancer Research Foundation (A.V. Lee, B.H. Park, and S. Oesterreich); Susan G. Komen Scholar awards (SAC110021 to A.V. Lee; SAC170078 to B.H. Park; SAC160073 to S. Oesterreich); the Metastatic Breast Cancer Network Foundation (S. Oesterreich); the NCI (R01CA221303 to S. Oesterreich; F30CA203154 to K.M. Levine; F30CA250167 to M.E. Yates); Department of Defense Breast Cancer Research Program (W81XWH1910434 to J. Gertz and W81XWH1910499 to S. Oesterreich), and the Fashion Footwear Association of New York, Magee-Womens Research Institute and Foundation, The Canney Foundation, The M&E Foundation, Nicole Meloche Foundation, Penguins Alumni Foundation, the Pennsylvania Breast Cancer Coalition, and the Shear Family Foundation. S. Oesterreich and A.V. Lee are Hillman Fellows. Z. Li is supported by John S. Lazo Cancer Pharmacology Fellowship. N. Tasdemir was supported by a Department of Defense Breakthrough Fellowship Award (BC160764) and an NIH Pathway to Independence Award (K99CA237736). This project used the UPMC Hillman Cancer Center Tissue and Research Pathology Services supported in part by NIH grant award P30CA047904. M.E. Yates reports grants from NIH during the conduct of the study. K.M. Levine reports grants from NIH during the conduct of the study. S. Ali reports grants from Cancer Research UK, Breast Cancer Now, and Medical Research Council UK during the conduct of the study; grants, personal fees, and other support from Carrick Therapeutics Ltd. and non-financial support and other support from AstraZeneca outside the submitted work. L. Buluwela reports grants from Cancer Research UK, Breast Cancer Now, and Medical Research Council UK during the conduct of the study; grants from Carrick Therapeutics Ltd. and non-financial support and other support from AstraZeneca outside the submitted work. J. Gertz reports grants from Department of Defense during the conduct of the study. L. Gerratana reports personal fees from Eli Lilly and Novartis during the conduct of the study. M. Cristofanilli reports grants and personal fees from Lilly, Menarini, Pfizer; personal fees from Foundation Medicine, Guardant Health, Olaris, and Cytodyn outside the submitted work. P. Sundd reports grants from Novartis AG, CSL Behring Inc, IHP Therapeutics, and Bayer Inc. outside the submitted work. E. Guerini-Rocco reports grants and nonfinancial support from Thermo Fisher Scientific; personal fees and non-financial support from Novartis, Roche; personal fees from Exact Sciences; and grants, personal fees, and non-financial support from AstraZeneca outside the submitted work. N. Wagle reports personal fees from Eli Lilly and Co., Relay Therapeutics, Flare Therapeutics, and grants from Puma Biotechnologies outside the submitted work. P. Jank reports other support from Myriad Genetics, Inc. outside the submitted work. C. Denkert reports personal fees from Roche, MSD Oncology, Daiichi Sankyo, AstraZeneca, Molecular Health, Lilly; grants from Myriad; and other support from Sividon outside the submitted work. M.M. Karsten reports personal fees from AstraZeneca and Roche outside the submitted work. B.H. Park is a paid consultant for Jackson Labs, EQRx, Sermonix, Hologics, Guardant Health and is a paid scientific advisory board member for Celcuity Inc. B.H. Park also has research contracts with GE Healthcare, Lilly, and Pfizer. Under separate licensing agreements between Horizon Discovery, LTD. and The Johns Hopkins University, B.H. Park is entitled to a share of royalties received by the University on sales of products. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. P.C. Lucas reports other support from NSABP Foundation and grants from NIH outside the submitted work; in addition, P.C. Lucas has a patent for Small Molecules and Their Use as MALT1 Inhibitors pending; and has received compensation from Schrodinger Inc. (speaker fee; spouse) and holds stock in Amgen, both outside the scope of submitted work. S. Oesterreich is married to Dr. Adrian Lee, co-author of the study. S. Oesterreich has obtained funding for the submitted work as indicated in the article; however, none of them represents a conflict of interest. No disclosures were reported by the other authors. The authors are grateful for advice, discussions, and technical support from Dr. Ye Qin, Dr. Yu Jiang, Dr. Min Yu, Yonatan Amzaleg, and Meghan S. Mooring. The authors would like to thank Dr. Peilu Wang for her contribution to earlier studies in the Lee-Oesterreich group on ESR1 mutations. This project used the University of Pittsburgh HSCRF Genomics Research Core, the University of Pittsburgh Center for Research Computing, and the UPMC Hillman Cancer Center Tissue and Research Pathology Services supported in part by NIH grant award 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.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Hotspot ESR1 Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis'. Together they form a unique fingerprint.

Cite this