Cargando…

Putative Breast Cancer Driver Mutations in TBX3 Cause Impaired Transcriptional Repression

The closely related T-box transcription factors TBX2 and TBX3 are frequently overexpressed in melanoma and various types of human cancers, in particular, breast cancer. The overexpression of TBX2 and TBX3 can have several cellular effects, among them suppression of senescence, promotion of epithelia...

Descripción completa

Detalles Bibliográficos
Autores principales: Fischer, Kathrin, Pflugfelder, Gert O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625211/
https://www.ncbi.nlm.nih.gov/pubmed/26579496
http://dx.doi.org/10.3389/fonc.2015.00244
_version_ 1782397956988600320
author Fischer, Kathrin
Pflugfelder, Gert O.
author_facet Fischer, Kathrin
Pflugfelder, Gert O.
author_sort Fischer, Kathrin
collection PubMed
description The closely related T-box transcription factors TBX2 and TBX3 are frequently overexpressed in melanoma and various types of human cancers, in particular, breast cancer. The overexpression of TBX2 and TBX3 can have several cellular effects, among them suppression of senescence, promotion of epithelial–mesenchymal transition, and invasive cell motility. In contrast, loss of function of TBX3 and most other human T-box genes causes developmental haploinsufficiency syndromes. Stephens and colleagues (1), by exome sequencing of breast tumor samples, identified five different mutations in TBX3, all affecting the DNA-binding T-domain. One in-frame deletion of a single amino acid, p.N212delN, was observed twice. Due to the clustering of these mutations to the T-domain and for statistical reasons, TBX3 was inferred to be a driver gene in breast cancer. Since mutations in the T-domain generally cause loss of function and because the tumorigenic action of TBX3 has generally been attributed to overexpression, we determined whether the putative driver mutations had loss- or gain-of-function properties. We tested two in-frame deletions, one missense, and one frameshift mutant protein for DNA-binding in vitro, and for target gene repression in cell culture. In addition, we performed an in silico analysis of somatic TBX mutations in breast cancer, collected in The Cancer Genome Atlas (TCGA). Both the experimental and the in silico analysis indicate that the observed mutations predominantly cause loss of TBX3 function.
format Online
Article
Text
id pubmed-4625211
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-46252112015-11-17 Putative Breast Cancer Driver Mutations in TBX3 Cause Impaired Transcriptional Repression Fischer, Kathrin Pflugfelder, Gert O. Front Oncol Oncology The closely related T-box transcription factors TBX2 and TBX3 are frequently overexpressed in melanoma and various types of human cancers, in particular, breast cancer. The overexpression of TBX2 and TBX3 can have several cellular effects, among them suppression of senescence, promotion of epithelial–mesenchymal transition, and invasive cell motility. In contrast, loss of function of TBX3 and most other human T-box genes causes developmental haploinsufficiency syndromes. Stephens and colleagues (1), by exome sequencing of breast tumor samples, identified five different mutations in TBX3, all affecting the DNA-binding T-domain. One in-frame deletion of a single amino acid, p.N212delN, was observed twice. Due to the clustering of these mutations to the T-domain and for statistical reasons, TBX3 was inferred to be a driver gene in breast cancer. Since mutations in the T-domain generally cause loss of function and because the tumorigenic action of TBX3 has generally been attributed to overexpression, we determined whether the putative driver mutations had loss- or gain-of-function properties. We tested two in-frame deletions, one missense, and one frameshift mutant protein for DNA-binding in vitro, and for target gene repression in cell culture. In addition, we performed an in silico analysis of somatic TBX mutations in breast cancer, collected in The Cancer Genome Atlas (TCGA). Both the experimental and the in silico analysis indicate that the observed mutations predominantly cause loss of TBX3 function. Frontiers Media S.A. 2015-10-29 /pmc/articles/PMC4625211/ /pubmed/26579496 http://dx.doi.org/10.3389/fonc.2015.00244 Text en Copyright © 2015 Fischer and Pflugfelder. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Fischer, Kathrin
Pflugfelder, Gert O.
Putative Breast Cancer Driver Mutations in TBX3 Cause Impaired Transcriptional Repression
title Putative Breast Cancer Driver Mutations in TBX3 Cause Impaired Transcriptional Repression
title_full Putative Breast Cancer Driver Mutations in TBX3 Cause Impaired Transcriptional Repression
title_fullStr Putative Breast Cancer Driver Mutations in TBX3 Cause Impaired Transcriptional Repression
title_full_unstemmed Putative Breast Cancer Driver Mutations in TBX3 Cause Impaired Transcriptional Repression
title_short Putative Breast Cancer Driver Mutations in TBX3 Cause Impaired Transcriptional Repression
title_sort putative breast cancer driver mutations in tbx3 cause impaired transcriptional repression
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625211/
https://www.ncbi.nlm.nih.gov/pubmed/26579496
http://dx.doi.org/10.3389/fonc.2015.00244
work_keys_str_mv AT fischerkathrin putativebreastcancerdrivermutationsintbx3causeimpairedtranscriptionalrepression
AT pflugfeldergerto putativebreastcancerdrivermutationsintbx3causeimpairedtranscriptionalrepression