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