Abstract
ERBB2 is an oncogenic driver with frequent gene mutations and amplification in human lung tumors and is an attractive target for lung cancer therapy. However, target therapies can be improved by understanding the in vivo mechanisms regulated by ERBB2 during lung tumor development. Here, we generated genetic mouse models to show that Erbb2 loss inhibited lung tumor development induced by deletion of Pten and Smad4. Transcriptome analysis showed that Erbb2 loss suppressed the significant changes of most of the induced genes by ablation of Pten and Smad4. Overlapping with ERBB2-associated human lung cancer genes further identified those ERBB2 downstream players potentially conserved in human and mouse lung tumors. Furthermore, MED24 was identified as a crucial oncogenic target of ERBB2 in lung tumor development. Taken together, ERBB2 is required for the dysregulation of cancer-related genes, such as MED24, during lung tumor development.
Highlights
Lung cancer is the leading cause of cancer death in the United States and worldwide [1,2].Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases and is the most common subtype of lung cancer [1]
Our previous study determined that Ptend/d Smad4d/d (CCSPiCre Ptend/d Smad4d/d ) mice developed lung tumors at 1 year of age with 100% incidence by activation of the ERBB2 pathway [12]
We generated Ptend/d Smad4d/d Erbb2d/d (CCSPiCre Ptend/d Smad4d/d Erbb2d/d ) mice to examine whether Erbb2 ablation inhibited lung tumor development induced by deletion of Pten and Smad4
Summary
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases and is the most common subtype of lung cancer [1]. NSCLS is further divided into adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma [1,2]. These tumor subtypes have distinct morphologies and molecular profiles [3,4]. The diversity of lung tumor subtypes makes it impossible for one drug to be effective on all lung cancer cell types [2]. Understanding the molecular profiles of lung tumors will significantly benefit lung cancer targeted therapy
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