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

doi:10.1016/j.celrep.2021.108822

Yongguang Yang, Marissa Leonard + Show 10 more

Open Access

https://doi.org/10.1016/j.celrep.2021.108822

Copy DOI

Abstract

SUMMARYMED1 (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.

Highlights

Breast cancer can be largely divided into multiple subtypes based on gene expression profile analyses (Perou et al, 2000; Cancer Genome Atlas Network, 2012)
Our studies further revealed that MED1 overexpression promotes epithelial-to-mesenchymal transition (EMT), cancer stem cell (CSC) formation, and the resistance to anti-HER2 therapy of mammary tumor virus (MMTV)-HER2 tumors
Generation and characterization of mammary-specific MED1 overexpression mice To study the role of MED1 overexpression in HER2-mediated tumorigenesis in vivo, we first generated an MMTV-MED1 transgenic mouse model overexpressing MED1 under the control of MMTV long-terminal repeat promoter/enhancer (Pierce et al, 1993) (Figure 1A)

Summary

Introduction

Breast cancer can be largely divided into multiple subtypes (e.g., estrogen receptor-positive [ER+] luminal A, ER+ luminal B, human epidermal growth factor receptor 2-positive [HER2+] and triple negative) based on gene expression profile analyses (Perou et al, 2000; Cancer Genome Atlas Network, 2012). Estrogen antagonists can effectively slow the growth of breast tumors and are used for prevention and treatment in ER+ breast cancer patients (Park and Jordan, 2002; O’Shaughnessy, 2006). HER2 amplification has been associated with aggressive disease, poor prognosis, and resistance to anti-estrogen therapy of ER+ breast cancer (Slamon et al, 1987; Osborne and Schiff, 2011). There is increasing evidence for the existence of multiple levels of crosstalk between ERa and HER2 signaling pathways in breast cancers, which lead to tumor progression and therapy resistance (Osborne and Schiff, 2011; Montemurro et al, 2013)

Methods

Results

Discussion

Conclusion