Functional cooperation between co-amplified genes promotes aggressive phenotypes of HER2-positive breast cancer
| Autor: | Elyse E. Lower, Jiang Wang, Gregory Bick, Chunmiao Cai, Syn Kok Yeo, Mingang Hao, Yongguang Yang, Zhenhua Luo, Marissa Leonard, Mahmoud Charif, Xiaoting Zhang, Jun-Lin Guan |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Receptor ErbB-2 MED1 Metastasis Transcriptome Mediator Complex Subunit 1 Mice 0302 clinical medicine Cell Movement Jab1 Neoplasm Metastasis RNA Small Interfering skin and connective tissue diseases lcsh:QH301-705.5 biology Phenotype Neoplastic Stem Cells Female RNA Interference therapeutic resistance Transcriptional Activation cancer stem cell Epithelial-Mesenchymal Transition Genetic Vectors Mice Nude Antineoplastic Agents General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Mediator Cancer stem cell HER2 medicine Animals Gene tumor metastasis COP9 Signalosome Complex Mouse mammary tumor virus Mammary Neoplasms Experimental Lapatinib biology.organism_classification medicine.disease 030104 developmental biology lcsh:Biology (General) Mammary Tumor Virus Mouse Cancer research 030217 neurology & neurosurgery Peptide Hydrolases |
| Zdroj: | Cell reports Cell Reports, Vol 34, Iss 10, Pp 108822-(2021) |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY MED1 (mediator subunit 1)co-amplifies with HER2, but its role in HER2-driven mammary tumorigenesis is still unknown. Here, we generate MED1 mammary-specific overexpression mice and cross them with mouse mammary tumor virus (MMTV)-HER2 mice. We observe significantly promoted onset, growth, metastasis, and multiplicity of HER2 tumors by MED1 overexpression. Further studies reveal critical roles for MED1 in epithelial-mesenchymal transition, cancer stem cell formation, and response to anti-HER2 therapy. Mechanistically, RNA sequencing (RNA-seq) transcriptome analyses and clinical sample correlation studies identify Jab1, a component of the COP9 signalosome complex, as the key direct target gene of MED1 contributing to these processes. Further studies reveal that Jab1 can also reciprocally regulate the stability and transcriptional activity of MED1. Together, our findings support a functional cooperation between these co-amplified genes in HER2+ mammary tumorigenesis and their potential usage as therapeutic targets for the treatment of HER2+ breast cancers. Graphical Abstract In brief In this study, Yang et al. generate a more clinically relevant MMTV-HER2/MMTV-MED1 mammary tumor mouse model and discover the critical roles and molecular mechanisms of MED1 overexpression in mediating the aggressive phenotypes of HER2+ tumor progression, metastasis, cancer stem cell formation, and therapy resistance. |
| Databáze: | OpenAIRE |
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