Cargando…

Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy

BACKGROUND: The epidermal specific ablation of Trp53 gene leads to the spontaneous development of aggressive tumors in mice through a process that is accelerated by the simultaneous ablation of Rb gene. Since alterations of p53-dependent pathway are common hallmarks of aggressive, poor prognostic hu...

Descripción completa

Detalles Bibliográficos
Autores principales: García-Escudero, Ramón, Martínez-Cruz, Ana B, Santos, Mirentxu, Lorz, Corina, Segrelles, Carmen, Garaulet, Guillermo, Saiz-Ladera, Cristina, Costa, Clotilde, Buitrago-Pérez, Águeda, Dueñas, Marta, Paramio, Jesús M
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913987/
https://www.ncbi.nlm.nih.gov/pubmed/20630075
http://dx.doi.org/10.1186/1476-4598-9-193
_version_ 1782184718301659136
author García-Escudero, Ramón
Martínez-Cruz, Ana B
Santos, Mirentxu
Lorz, Corina
Segrelles, Carmen
Garaulet, Guillermo
Saiz-Ladera, Cristina
Costa, Clotilde
Buitrago-Pérez, Águeda
Dueñas, Marta
Paramio, Jesús M
author_facet García-Escudero, Ramón
Martínez-Cruz, Ana B
Santos, Mirentxu
Lorz, Corina
Segrelles, Carmen
Garaulet, Guillermo
Saiz-Ladera, Cristina
Costa, Clotilde
Buitrago-Pérez, Águeda
Dueñas, Marta
Paramio, Jesús M
author_sort García-Escudero, Ramón
collection PubMed
description BACKGROUND: The epidermal specific ablation of Trp53 gene leads to the spontaneous development of aggressive tumors in mice through a process that is accelerated by the simultaneous ablation of Rb gene. Since alterations of p53-dependent pathway are common hallmarks of aggressive, poor prognostic human cancers, these mouse models can recapitulate the molecular features of some of these human malignancies. RESULTS: To evaluate this possibility, gene expression microarray analysis was performed in mouse samples. The mouse tumors display increased expression of cell cycle and chromosomal instability associated genes. Remarkably, they are also enriched in human embryonic stem cell gene signatures, a characteristic feature of human aggressive tumors. Using cross-species comparison and meta-analytical approaches, we also observed that spontaneous mouse tumors display robust similarities with gene expression profiles of human tumors bearing mutated TP53, or displaying poor prognostic outcome, from multiple body tissues. We have obtained a 20-gene signature whose genes are overexpressed in mouse tumors and can identify human tumors with poor outcome from breast cancer, astrocytoma and multiple myeloma. This signature was consistently overexpressed in additional mouse tumors using microarray analysis. Two of the genes of this signature, AURKA and UBE2C, were validated in human breast and cervical cancer as potential biomarkers of malignancy. CONCLUSIONS: Our analyses demonstrate that these mouse models are promising preclinical tools aimed to search for malignancy biomarkers and to test targeted therapies of prospective use in human aggressive tumors and/or with p53 mutation or inactivation.
format Text
id pubmed-2913987
institution National Center for Biotechnology Information
language English
publishDate 2010
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-29139872010-08-03 Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy García-Escudero, Ramón Martínez-Cruz, Ana B Santos, Mirentxu Lorz, Corina Segrelles, Carmen Garaulet, Guillermo Saiz-Ladera, Cristina Costa, Clotilde Buitrago-Pérez, Águeda Dueñas, Marta Paramio, Jesús M Mol Cancer Research BACKGROUND: The epidermal specific ablation of Trp53 gene leads to the spontaneous development of aggressive tumors in mice through a process that is accelerated by the simultaneous ablation of Rb gene. Since alterations of p53-dependent pathway are common hallmarks of aggressive, poor prognostic human cancers, these mouse models can recapitulate the molecular features of some of these human malignancies. RESULTS: To evaluate this possibility, gene expression microarray analysis was performed in mouse samples. The mouse tumors display increased expression of cell cycle and chromosomal instability associated genes. Remarkably, they are also enriched in human embryonic stem cell gene signatures, a characteristic feature of human aggressive tumors. Using cross-species comparison and meta-analytical approaches, we also observed that spontaneous mouse tumors display robust similarities with gene expression profiles of human tumors bearing mutated TP53, or displaying poor prognostic outcome, from multiple body tissues. We have obtained a 20-gene signature whose genes are overexpressed in mouse tumors and can identify human tumors with poor outcome from breast cancer, astrocytoma and multiple myeloma. This signature was consistently overexpressed in additional mouse tumors using microarray analysis. Two of the genes of this signature, AURKA and UBE2C, were validated in human breast and cervical cancer as potential biomarkers of malignancy. CONCLUSIONS: Our analyses demonstrate that these mouse models are promising preclinical tools aimed to search for malignancy biomarkers and to test targeted therapies of prospective use in human aggressive tumors and/or with p53 mutation or inactivation. BioMed Central 2010-07-14 /pmc/articles/PMC2913987/ /pubmed/20630075 http://dx.doi.org/10.1186/1476-4598-9-193 Text en Copyright ©2010 García-Escudero et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
García-Escudero, Ramón
Martínez-Cruz, Ana B
Santos, Mirentxu
Lorz, Corina
Segrelles, Carmen
Garaulet, Guillermo
Saiz-Ladera, Cristina
Costa, Clotilde
Buitrago-Pérez, Águeda
Dueñas, Marta
Paramio, Jesús M
Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy
title Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy
title_full Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy
title_fullStr Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy
title_full_unstemmed Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy
title_short Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy
title_sort gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913987/
https://www.ncbi.nlm.nih.gov/pubmed/20630075
http://dx.doi.org/10.1186/1476-4598-9-193
work_keys_str_mv AT garciaescuderoramon geneexpressionprofilingofmousep53deficientepidermalcarcinomadefinesmoleculardeterminantsofhumancancermalignancy
AT martinezcruzanab geneexpressionprofilingofmousep53deficientepidermalcarcinomadefinesmoleculardeterminantsofhumancancermalignancy
AT santosmirentxu geneexpressionprofilingofmousep53deficientepidermalcarcinomadefinesmoleculardeterminantsofhumancancermalignancy
AT lorzcorina geneexpressionprofilingofmousep53deficientepidermalcarcinomadefinesmoleculardeterminantsofhumancancermalignancy
AT segrellescarmen geneexpressionprofilingofmousep53deficientepidermalcarcinomadefinesmoleculardeterminantsofhumancancermalignancy
AT garauletguillermo geneexpressionprofilingofmousep53deficientepidermalcarcinomadefinesmoleculardeterminantsofhumancancermalignancy
AT saizladeracristina geneexpressionprofilingofmousep53deficientepidermalcarcinomadefinesmoleculardeterminantsofhumancancermalignancy
AT costaclotilde geneexpressionprofilingofmousep53deficientepidermalcarcinomadefinesmoleculardeterminantsofhumancancermalignancy
AT buitragoperezagueda geneexpressionprofilingofmousep53deficientepidermalcarcinomadefinesmoleculardeterminantsofhumancancermalignancy
AT duenasmarta geneexpressionprofilingofmousep53deficientepidermalcarcinomadefinesmoleculardeterminantsofhumancancermalignancy
AT paramiojesusm geneexpressionprofilingofmousep53deficientepidermalcarcinomadefinesmoleculardeterminantsofhumancancermalignancy