An In Vivo Gain-of-Function Screen Identifies the Williams-Beuren Syndrome Gene GTF2IRD1 as a Mammary Tumor Promoter.

Huo Y, Su T, Cai Q, Macara IG
Cell Rep. 2016 15 (10): 2089-2096

PMID: 27239038 · PMCID: PMC5412078 · DOI:10.1016/j.celrep.2016.05.011

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.

Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

MeSH Terms (17)

Animals Bone Morphogenetic Protein Receptors, Type I Breast Neoplasms Carcinogenesis Female Gene Expression Regulation, Neoplastic Genetic Testing Humans Mammary Neoplasms, Animal Mice, Transgenic Muscle Proteins Nuclear Proteins Protein-Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta Trans-Activators Williams Syndrome

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