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

Cell Rep. 2016 Jun 7;15(10):2089-2096. doi: 10.1016/j.celrep.2016.05.011. Epub 2016 May 26.

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.

MeSH terms

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

Substances

  • GTF2IRD1 protein, human
  • Gtf2ird1 protein, mouse
  • Muscle Proteins
  • Nuclear Proteins
  • Receptors, Transforming Growth Factor beta
  • Trans-Activators
  • Protein Serine-Threonine Kinases
  • Bmpr1b protein, mouse
  • Bone Morphogenetic Protein Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type II