Megan E Yates, Hunter Waltermire, Kanako Mori, Zheqi Li, Yiting Li, Hannah Guzolik, Xiaosong Wang, Tiantong Liu, Jennifer M Atkinson, Jagmohan Hooda, Adrian V Lee, Steffi Oesterreich
{"title":"ESR1 Fusions Invoke Breast Cancer Subtype-Dependent Enrichment of Ligand-Independent Oncogenic Signatures and Phenotypes.","authors":"Megan E Yates, Hunter Waltermire, Kanako Mori, Zheqi Li, Yiting Li, Hannah Guzolik, Xiaosong Wang, Tiantong Liu, Jennifer M Atkinson, Jagmohan Hooda, Adrian V Lee, Steffi Oesterreich","doi":"10.1210/endocr/bqae111","DOIUrl":null,"url":null,"abstract":"<p><p>Breast cancer is a leading cause of female mortality and despite advancements in personalized therapeutics, metastatic disease largely remains incurable due to drug resistance. The estrogen receptor (ER, ESR1) is expressed in two-thirds of all breast cancer, and under endocrine stress, somatic ESR1 mutations arise in approximately 30% of cases that result in endocrine resistance. We and others reported ESR1 fusions as a mechanism of ER-mediated endocrine resistance. ER fusions, which retain the activation function 1- and DNA-binding domains, harbor ESR1 exons 1 to 6 fused to an in-frame gene partner resulting in loss of the ER ligand-binding domain (LBD). We demonstrate that in a no-special type (invasive ductal carcinoma [IDC]-NST) and an invasive lobular carcinoma (ILC) cell line, ER fusions exhibit robust hyperactivation of canonical ER signaling pathways independent of estradiol or antiendocrine therapies. We employ cell line models stably overexpressing ER fusions with concurrent endogenous ER knockdown to minimize endogenous ER influence. Cell lines exhibited shared transcriptomic enrichment in pathways known to be drivers of metastatic disease, notably MYC signaling. Cells expressing the 3' fusion partners SOX9 and YAP1 consistently demonstrated enhanced growth and cell survival. ILC cells expressing the DAB2 fusion led to enhanced growth, survival, and migration, phenotypes not appreciated in the IDC-NST DAB2 model. Herein, we report that cell line activity is subtype-, fusion-, and assay-specific, suggesting that LBD loss, the fusion partner, and the cellular landscape all influence fusion activities. Therefore, it will be critical to assess fusion frequency in the context of the clinicopathology.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8000,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11384147/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Endocrinology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1210/endocr/bqae111","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
Abstract
Breast cancer is a leading cause of female mortality and despite advancements in personalized therapeutics, metastatic disease largely remains incurable due to drug resistance. The estrogen receptor (ER, ESR1) is expressed in two-thirds of all breast cancer, and under endocrine stress, somatic ESR1 mutations arise in approximately 30% of cases that result in endocrine resistance. We and others reported ESR1 fusions as a mechanism of ER-mediated endocrine resistance. ER fusions, which retain the activation function 1- and DNA-binding domains, harbor ESR1 exons 1 to 6 fused to an in-frame gene partner resulting in loss of the ER ligand-binding domain (LBD). We demonstrate that in a no-special type (invasive ductal carcinoma [IDC]-NST) and an invasive lobular carcinoma (ILC) cell line, ER fusions exhibit robust hyperactivation of canonical ER signaling pathways independent of estradiol or antiendocrine therapies. We employ cell line models stably overexpressing ER fusions with concurrent endogenous ER knockdown to minimize endogenous ER influence. Cell lines exhibited shared transcriptomic enrichment in pathways known to be drivers of metastatic disease, notably MYC signaling. Cells expressing the 3' fusion partners SOX9 and YAP1 consistently demonstrated enhanced growth and cell survival. ILC cells expressing the DAB2 fusion led to enhanced growth, survival, and migration, phenotypes not appreciated in the IDC-NST DAB2 model. Herein, we report that cell line activity is subtype-, fusion-, and assay-specific, suggesting that LBD loss, the fusion partner, and the cellular landscape all influence fusion activities. Therefore, it will be critical to assess fusion frequency in the context of the clinicopathology.
期刊介绍:
The mission of Endocrinology is to be the authoritative source of emerging hormone science and to disseminate that new knowledge to scientists, clinicians, and the public in a way that will enable "hormone science to health." Endocrinology welcomes the submission of original research investigating endocrine systems and diseases at all levels of biological organization, incorporating molecular mechanistic studies, such as hormone-receptor interactions, in all areas of endocrinology, as well as cross-disciplinary and integrative studies. The editors of Endocrinology encourage the submission of research in emerging areas not traditionally recognized as endocrinology or metabolism in addition to the following traditionally recognized fields: Adrenal; Bone Health and Osteoporosis; Cardiovascular Endocrinology; Diabetes; Endocrine-Disrupting Chemicals; Endocrine Neoplasia and Cancer; Growth; Neuroendocrinology; Nuclear Receptors and Their Ligands; Obesity; Reproductive Endocrinology; Signaling Pathways; and Thyroid.