Abstract
BackgroundThe 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.ResultsTo 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.ConclusionsOur 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.
Highlights
Mouse models of human cancer have become essential tools for preclinical analysis of antitumoral drug discovery
To fully characterize the molecular features of these tumors we performed gene expression profiling using Affymetrix microarrays using total RNA from 27 carcinomas arising in Trp53ΔEC and RbΔEC; Trp53ΔEC mice, and 9 normal, wild type skin samples
Gene expression comparison of tumours arising in Trp53ΔEC and RbΔEC; Trp53ΔEC mouse models In both genotypes the tumors appeared as small subcutaneous squamous lesions originating in or close to the hair follicles (Fig. 1a)
Summary
Mouse models of human cancer have become essential tools for preclinical analysis of antitumoral drug discovery. To demonstrate that these models faithfully recapitulate human disease, a deep characterization of the tumors is required. Functional comparative genomics is one of the most powerful techniques for such validation. Such analyses have evidenced that mouse models display the complexity of human cancer genomes. Since alterations of p53dependent pathway are common hallmarks of aggressive, poor prognostic human cancers, these mouse models can recapitulate the molecular features of some of these human malignancies
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