title: ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis.
abstract: Lung cancer remains the leading cause of cancer death. Genome sequencing of lung tumors from patients with squamous cell carcinoma has identified SMAD4 to be frequently mutated. Here, we use a mouse model to determine the molecular mechanisms by which Smad4 loss leads to lung cancer progression. Mice with ablation of Pten and Smad4 in airway epithelium develop metastatic adenosquamous tumors. Comparative transcriptomic and in vivo cistromic analyses determine that loss of PTEN and SMAD4 results in ELF3 and ErbB2 pathway activation due to decreased expression of ERRFI1, a negative regulator of ERBB2 in mouse and human cells. The combinatorial inhibition of ErbB2 and Akt signaling attenuate tumor progression and cell invasion, respectively. Expression profile analysis of human lung tumors substantiated the importance of the ErbB2/Akt/ELF3 signaling pathway as both a prognostic biomarker and a therapeutic drug target for treating lung cancer.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sung-Nam
authors.initials: SN
authors.lastname: Cho
authors.affiliation: Department of Medicine, Pulmonary and Critical Care, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bindu
authors.initials: B
authors.lastname: Akkanti
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Nili
authors.initials: N
authors.lastname: Jin
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Mao
authors.affiliation: Department of Biochemistry & Molecular Biology, Wright State University, Dayton, OH 45435, USA.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Long
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Tenghui
authors.initials: T
authors.lastname: Chen
authors.affiliation: The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ximing
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistub
authors.affiliation: The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Departments of Medicine, Hematology and Oncology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Department of Medicine, Pulmonary and Critical Care, Baylor College of Medicine, Houston, TX 77030, USA; The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Farrah
authors.initials: F
authors.lastname: Kheradmand
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: fdemayo@bcm.edu.
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo