Hotspot ESR1 mutations are multimodal and contextual drivers of breast cancer metastasis
Hotspot ESR1 mutations are multimodal and contextual drivers of breast cancer metastasis
Abstract Constitutively active estrogen receptor-α (ER/ESR1) mutations have been identified in approximately one third of ER+ metastatic breast cancer. Although these mutations are known 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 concordance with transcriptomic profiling of ESR1 mutant tumors, genome-edited Y537S and D538G cell models have a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally confers enhanced cell-cell contacts while decreased cell-ECM adhesion. Context-dependent migratory phenotypes revealed co-targeting of Wnt and ER as vulnerability. Mutant ESR1 exhibits non-canonical regulation of several metastatic pathways including secondary transactivation and de novo FOXA1-driven chromatin remodeling. Collectively, our data supports evidence for ESR1 mutation-driven metastases and provides insight for future preclinical therapeutic strategies. SignificanceContext and allele-dependent transcriptome and cistrome reprogramming in genome-edited ESR1 mutation cell models elicit diverse metastatic phenotypes, including but not limited to alterations in cell adhesion and migration. The gain-of-function mutations can be pharmacologically targeted, and thus may be key components of novel therapeutic treatment strategies for ER-mutant metastatic breast cancer.
Zhu Li、Lucas Peter C.、Tseng George C.、Oesterreich Steffi、Yates Megan E.、Tasdemir Nilgun、Chen Jian、Buluwela Laki、Richer Jennifer K.、Zhang Qiang、Cristofanilli Massimo、Wagle Nikhil、Jank Paul、Atkinson Jennifer M.、Wallace Callen T.、Bahreini Amir、Ali Simak、Carroll Jason S.、Li Zheqi、Watkins Simon C.、Karsten Maria M、Arnesen Spencer、Troness Benjamin、Gertz Jason、Lee Adrian V.、Sundd Prithu、Priedigkeit Nolan M.、El-Ashry Dorraya、Wu Yang、Denkert Carsten、Levine Kevin M.、Montanez Maritza A.、Zhang Youbin、Park Ben H.、Gerratana Lorenzo、Blohmer Jens-Uwe
Department of Biostatistics, University of PittsburghDepartment of Pathology, University of PittsburghDepartment of Biostatistics, University of PittsburghDepartment of Pharmacology and Chemical Biology, University of Pittsburgh||Women?ˉs Cancer Research Center, Magee Women?ˉs Research Institute, UPMC Hillman Cancer Center||Integrative Systems Biology Program, University of Pittsburgh||Department of Human Genetics, University of Pittsburgh||Department of Pathology, University of PittsburghWomen?ˉs Cancer Research Center, Magee Women?ˉs Research Institute, UPMC Hillman Cancer Center||Integrative Systems Biology Program, University of Pittsburgh||Medical Scientist Training Program, University of Pittsburgh School of MedicineDepartment of Pharmacology and Chemical Biology, University of Pittsburgh||Women?ˉs Cancer Research Center, Magee Women?ˉs Research Institute, UPMC Hillman Cancer CenterWomen?ˉs Cancer Research Center, Magee Women?ˉs Research Institute, UPMC Hillman Cancer CenterDepartment of Surgery and Cancer, Imperial College LondonDepartment of Pathology, University of Colorado Anschutz Medical CampusRobert H. Lurie Cancer Center of Northwestern University, Feinberg School of MedicineRobert H. Lurie Cancer Center of Northwestern University, Feinberg School of MedicineDepartment of Medical Oncology and Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Brigham and Women?ˉs HospitalInstitut of Pathology, Philipps-University Marburg, UKGM - Universit?tsklinikum MarburgDepartment of Pharmacology and Chemical Biology, University of Pittsburgh||Women?ˉs Cancer Research Center, Magee Women?ˉs Research Institute, UPMC Hillman Cancer CenterCenter for Biological Imaging, University of PittsburghWomen?ˉs Cancer Research Center, Magee Women?ˉs Research Institute, UPMC Hillman Cancer Center||Department of Human Genetics, University of PittsburghDepartment of Surgery and Cancer, Imperial College LondonCancer Research UK, Cambridge Institute, University of CambridgeDepartment of Pharmacology and Chemical Biology, University of Pittsburgh||Women?ˉs Cancer Research Center, Magee Women?ˉs Research Institute, UPMC Hillman Cancer CenterCenter for Biological Imaging, University of PittsburghDepartment of Gynecology with Breast Center, Charit¨| ¨C Universit?tsmedizin Berlin, Corporate member of Freie Universit?t Berlin, Humbold-Univerist?t zu Berlin and Berlin Institute of HealthDepartment of Oncological Sciences, University of Utah||Huntsman Cancer Institute, University of UtahUniversity of Minnesota Masonic Cancer CenterDepartment of Oncological Sciences, University of Utah||Huntsman Cancer Institute, University of UtahDepartment of Pharmacology and Chemical Biology, University of Pittsburgh||Women?ˉs Cancer Research Center, Magee Women?ˉs Research Institute, UPMC Hillman Cancer Center||Integrative Systems Biology Program, University of Pittsburgh||Department of Human Genetics, University of PittsburghPittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of MedicineDepartment of Pharmacology and Chemical Biology, University of Pittsburgh||Women?ˉs Cancer Research Center, Magee Women?ˉs Research Institute, UPMC Hillman Cancer CenterUniversity of Minnesota Masonic Cancer CenterWomen?ˉs Cancer Research Center, Magee Women?ˉs Research Institute, UPMC Hillman Cancer Center||School of Medicine, Tsinghua UniversityInstitut of Pathology, Philipps-University Marburg, UKGM - Universit?tsklinikum MarburgWomen?ˉs Cancer Research Center, Magee Women?ˉs Research Institute, UPMC Hillman Cancer Center||Department of Pathology, University of PittsburghPittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of MedicineRobert H. Lurie Cancer Center of Northwestern University, Feinberg School of MedicineVanderbilt University Ingraham Cancer CenterRobert H. Lurie Cancer Center of Northwestern University, Feinberg School of Medicine||Department of Medicine (DAME) University of UdineDepartment of Gynecology with Breast Center, Charit¨| ¨C Universit?tsmedizin Berlin, Corporate member of Freie Universit?t Berlin, Humbold-Univerist?t zu Berlin and Berlin Institute of Health
肿瘤学基础医学分子生物学
ESR1 mutationsMetastasisCell AdhesionMigrationBreast cancer
Zhu Li,Lucas Peter C.,Tseng George C.,Oesterreich Steffi,Yates Megan E.,Tasdemir Nilgun,Chen Jian,Buluwela Laki,Richer Jennifer K.,Zhang Qiang,Cristofanilli Massimo,Wagle Nikhil,Jank Paul,Atkinson Jennifer M.,Wallace Callen T.,Bahreini Amir,Ali Simak,Carroll Jason S.,Li Zheqi,Watkins Simon C.,Karsten Maria M,Arnesen Spencer,Troness Benjamin,Gertz Jason,Lee Adrian V.,Sundd Prithu,Priedigkeit Nolan M.,El-Ashry Dorraya,Wu Yang,Denkert Carsten,Levine Kevin M.,Montanez Maritza A.,Zhang Youbin,Park Ben H.,Gerratana Lorenzo,Blohmer Jens-Uwe.Hotspot ESR1 mutations are multimodal and contextual drivers of breast cancer metastasis[EB/OL].(2025-03-28)[2025-05-10].https://www.biorxiv.org/content/10.1101/2021.02.10.430701.点此复制
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