title: An In Vivo Gain-of-Function Screen Identifies the Williams-Beuren Syndrome Gene GTF2IRD1 as a Mammary Tumor Promoter.
abstract: The broad implementation of precision medicine in cancer is impeded by the lack of a complete inventory of the genes involved in tumorigenesis. We performed in vivo screening of ∼1,000 genes that are associated with signaling for positive roles in breast cancer, using lentiviral expression vectors in primary MMTV-ErbB2 mammary tissue. Gain of function of five genes, including RET, GTF2IRD1, ADORA1, LARS2, and DPP8, significantly promoted mammary tumor growth. We further studied one tumor-promoting gene, the transcription factor GTF2IRD1. The mis-regulation of genes downstream of GTF2IRD1, including TβR2 and BMPR1b, also individually promoted mammary cancer development, and silencing of TβR2 suppressed GTF2IRD1-driven tumor promotion. In addition, GTF2IRD1 is highly expressed in human breast tumors, correlating with high tumor grades and poor prognosis. Our in vivo approach is readily expandable to whole-genome annotation of tumor-promoting genes.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Huo
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Su
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Qiuyin
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: ian.g.macara@vanderbilt.edu.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Macara
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005820:Genetic Testing; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D018980:Williams Syndrome / Q000235:genetics* / Q000473:pathology
chemical_list: C405493:GTF2IRD1 protein, human; C486558:Gtf2ird1 protein, mouse; D009124:Muscle Proteins; D009687:Nuclear Proteins; D018125:Receptors, Transforming Growth Factor beta; D015534:Trans-Activators; D017346:Protein Serine-Threonine Kinases; C498215:Bmpr1b protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II