Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Roberto Rangel; Song-Choon Lee; Kenneth Hon-Kim Ban; Liliana Guzman-Rojas; Michael B Mann; Justin Y Newberg; Takahiro Kodama; Leslie A McNoe; Luxmanan Selvanesan; Jerrold M Ward; Alistair G Rust; Kuan-Yew Chin; Michael A Black; Nancy A Jenkins; Neal G Copeland

doi:10.1073/pnas.1613859113

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7749-E7758. doi: 10.1073/pnas.1613859113. Epub 2016 Nov 14.

Authors

Roberto Rangel¹, Song-Choon Lee², Kenneth Hon-Kim Ban^{2

3}, Liliana Guzman-Rojas¹, Michael B Mann¹, Justin Y Newberg¹, Takahiro Kodama¹, Leslie A McNoe⁴, Luxmanan Selvanesan⁴, Jerrold M Ward², Alistair G Rust⁵, Kuan-Yew Chin², Michael A Black⁴, Nancy A Jenkins^{1

2}, Neal G Copeland^{6

2}

Affiliations

¹ Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030.
² Division of Genomics and Genetics, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Biopolis, Singapore 138673.
³ Deparment of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 138673.
⁴ Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand.
⁵ Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, United Kingdom.
⁶ Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030; [email protected].

Abstract

Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1 Down-regulation of TRPS1 in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression of SERPINE1 and SERPINB2 and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.

Keywords: Sleeping Beauty; TRPS1; breast cancer; metastasis; tumor suppressors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics*
Adenocarcinoma / secondary
Animals
Cell Line, Tumor
DNA Transposable Elements*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Disease Progression
Female
Gene Expression
Gene Expression Regulation, Neoplastic
Genes, Neoplasm
Genes, Tumor Suppressor
Humans
Kaplan-Meier Estimate
Lung Neoplasms
Mammary Neoplasms, Experimental / genetics*
Mammary Neoplasms, Experimental / pathology
Mice, Transgenic
Mutagenesis
Mutation, Missense
PTEN Phosphohydrolase / genetics*
Proportional Hazards Models
Proto-Oncogene Proteins c-fos / genetics
Proto-Oncogene Proteins c-fos / metabolism
Repressor Proteins
Transcription Factors / genetics
Transcription Factors / metabolism
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / mortality
Triple Negative Breast Neoplasms / pathology

Substances

DNA Transposable Elements
DNA-Binding Proteins
Proto-Oncogene Proteins c-fos
Repressor Proteins
TRPS1 protein, human
Transcription Factors
fos-related antigen 1
PTEN Phosphohydrolase
Pten protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding