Functional cooperation between co-amplified genes promotes aggressive phenotypes of HER2-positive breast cancer
Yongguang Yang,
Marissa Leonard,
Zhenhua Luo,
Syn Yeo,
Gregory Bick,
Mingang Hao,
Chunmiao Cai,
Mahmoud Charif,
Jiang Wang,
Jun-Lin Guan,
Elyse E. Lower,
Xiaoting Zhang
Affiliations
Yongguang Yang
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Marissa Leonard
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Graduate Program in Cancer and Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Zhenhua Luo
The Liver Care Center and Divisions of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Syn Yeo
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Gregory Bick
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Mingang Hao
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Chunmiao Cai
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Mahmoud Charif
Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Jiang Wang
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Jun-Lin Guan
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Elyse E. Lower
Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Xiaoting Zhang
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Graduate Program in Cancer and Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; University of Cincinnati Cancer Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Corresponding author
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.
