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

García-Escudero R, Martínez-Cruz AB, Santos M, Lorz C, Segrelles C, Garaulet G, Saiz-Ladera C, Costa C, Buitrago-Pérez A, Dueñas M, Paramio JM - Mol. Cancer (2010)

Bottom Line: 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.Remarkably, they are also enriched in human embryonic stem cell gene signatures, a characteristic feature of human aggressive tumors.Two of the genes of this signature, AURKA and UBE2C, were validated in human breast and cervical cancer as potential biomarkers of malignancy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Oncology Unit, Division of Biomedicine, CIEMAT, Ave, Complutense 22, E-28040 Madrid, Spain. ramon.garcia@ciemat.es

ABSTRACT

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.

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Overlapping of mouse and human tumors. (a) Gene expression overlapping between mouse tumors and human samples with TP53 mutations from 7 different cancer types is shown. n: total number of human tumors analyzed. Bar plots represent the significance of the overlap between overexpressed genes in tumors of p53-deficient mouse and genes overexpressed in human tumor samples with TP53 mutations (p-val, Fisher's exact test). Numbers at left represent the gene number overlap. Aside the plot is represented the color codes for each cancer tissue. Asterisk represents the most significant overlapping. (b) Mouse tumors as models for missense and truncating TP53 mutations. Gene expression values of the 98 genes overlapping between the mouse tumors and the breast cancer samples from Ivshina et al. [26] (asterisk in panel a) with TP53 mutations (overlapping score; mean = 0, stdv = 1) were plotted depending on the TP53 mutation status (left) or the mutation type (right). Number of tumor samples and significance of mean difference is shown. (c) Gene expression overlapping between mouse tumors and human samples with poor outcome from 11 different cancer types is shown. n: total number of human tumors analyzed. Bar plots represent the significance of the overlap between overexpressed genes in tumors of p53-deficient mouse and genes overexpressed in human tumor samples with poor outcome (p-val, Fisher's exact test). Numbers at left represent the gene number overlap. Aside the plot is represented the color codes for each cancer tissue.
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Figure 4: Overlapping of mouse and human tumors. (a) Gene expression overlapping between mouse tumors and human samples with TP53 mutations from 7 different cancer types is shown. n: total number of human tumors analyzed. Bar plots represent the significance of the overlap between overexpressed genes in tumors of p53-deficient mouse and genes overexpressed in human tumor samples with TP53 mutations (p-val, Fisher's exact test). Numbers at left represent the gene number overlap. Aside the plot is represented the color codes for each cancer tissue. Asterisk represents the most significant overlapping. (b) Mouse tumors as models for missense and truncating TP53 mutations. Gene expression values of the 98 genes overlapping between the mouse tumors and the breast cancer samples from Ivshina et al. [26] (asterisk in panel a) with TP53 mutations (overlapping score; mean = 0, stdv = 1) were plotted depending on the TP53 mutation status (left) or the mutation type (right). Number of tumor samples and significance of mean difference is shown. (c) Gene expression overlapping between mouse tumors and human samples with poor outcome from 11 different cancer types is shown. n: total number of human tumors analyzed. Bar plots represent the significance of the overlap between overexpressed genes in tumors of p53-deficient mouse and genes overexpressed in human tumor samples with poor outcome (p-val, Fisher's exact test). Numbers at left represent the gene number overlap. Aside the plot is represented the color codes for each cancer tissue.

Mentions: To test whether the gene expression patterns that characterize Trp53ΔEC and RbΔEC; Trp53ΔEC mouse tumors (training dataset) are also present in human cancers with TP53 mutations and/or with poor clinical outcome, we performed an exhaustive comparison of the mouse tumor signature (682-probesets) with gene datasets of human cancer samples using the Oncomine human cancer genomics database (see Materials and Methods) [24,25]. First we analyzed the genes overexpressed in the mouse tumors (371 probesets), and compared them with the overexpressed genes in human samples bearing TP53 mutations. This meta-analysis showed a very significant overlap with many human epithelial and non-epithelial cancers, indicating that multiple genes overexpressed in the mouse epidermal tumors are in common with human tumors from distinct body sites and characterized by bearing mutant TP53 gene (Fig. 4a and Additional file 4). To study the existence of possible correlation with different types of p53 mutations in human tumors, we analyzed in further detail a breast cancer dataset containing gene expression and p53 mutation data of 247 patients [26], and which also showed the highest overlapping significance in the human p53-mutant tumors panel (asterisk in Fig. 4a) (98 overlapping genes, p-val = 1.6 × 10-66). As a measure of the status similarity with respect to mouse tumors, we calculated an overlapping score of each breast cancer sample (see Materials and Methods) and represented it as a function of TP53 mutational status. The mean differences and significance were calculated as the tumors were grouped by TP53 mutation status (mutant or wild type) or by mutation type (missense or truncating). As expected, the differences were highly significant between tumor samples bearing TP53 mutation or wild type (Fig. 4b, left panel), demonstrating that the mouse tumors expression profile could distinguish between both types of human tumors. Furthermore, the mean values were also significantly higher in the samples with truncating mutations when compared with missense mutations (Fig. 4b, right panel). Overall these analyses suggest that mouse tumors with somatic deficiency of both p53 alleles resemble human tumors with TP53 mutations, especially tumors that can produce truncated p53 proteins.


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

García-Escudero R, Martínez-Cruz AB, Santos M, Lorz C, Segrelles C, Garaulet G, Saiz-Ladera C, Costa C, Buitrago-Pérez A, Dueñas M, Paramio JM - Mol. Cancer (2010)

Overlapping of mouse and human tumors. (a) Gene expression overlapping between mouse tumors and human samples with TP53 mutations from 7 different cancer types is shown. n: total number of human tumors analyzed. Bar plots represent the significance of the overlap between overexpressed genes in tumors of p53-deficient mouse and genes overexpressed in human tumor samples with TP53 mutations (p-val, Fisher's exact test). Numbers at left represent the gene number overlap. Aside the plot is represented the color codes for each cancer tissue. Asterisk represents the most significant overlapping. (b) Mouse tumors as models for missense and truncating TP53 mutations. Gene expression values of the 98 genes overlapping between the mouse tumors and the breast cancer samples from Ivshina et al. [26] (asterisk in panel a) with TP53 mutations (overlapping score; mean = 0, stdv = 1) were plotted depending on the TP53 mutation status (left) or the mutation type (right). Number of tumor samples and significance of mean difference is shown. (c) Gene expression overlapping between mouse tumors and human samples with poor outcome from 11 different cancer types is shown. n: total number of human tumors analyzed. Bar plots represent the significance of the overlap between overexpressed genes in tumors of p53-deficient mouse and genes overexpressed in human tumor samples with poor outcome (p-val, Fisher's exact test). Numbers at left represent the gene number overlap. Aside the plot is represented the color codes for each cancer tissue.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 4: Overlapping of mouse and human tumors. (a) Gene expression overlapping between mouse tumors and human samples with TP53 mutations from 7 different cancer types is shown. n: total number of human tumors analyzed. Bar plots represent the significance of the overlap between overexpressed genes in tumors of p53-deficient mouse and genes overexpressed in human tumor samples with TP53 mutations (p-val, Fisher's exact test). Numbers at left represent the gene number overlap. Aside the plot is represented the color codes for each cancer tissue. Asterisk represents the most significant overlapping. (b) Mouse tumors as models for missense and truncating TP53 mutations. Gene expression values of the 98 genes overlapping between the mouse tumors and the breast cancer samples from Ivshina et al. [26] (asterisk in panel a) with TP53 mutations (overlapping score; mean = 0, stdv = 1) were plotted depending on the TP53 mutation status (left) or the mutation type (right). Number of tumor samples and significance of mean difference is shown. (c) Gene expression overlapping between mouse tumors and human samples with poor outcome from 11 different cancer types is shown. n: total number of human tumors analyzed. Bar plots represent the significance of the overlap between overexpressed genes in tumors of p53-deficient mouse and genes overexpressed in human tumor samples with poor outcome (p-val, Fisher's exact test). Numbers at left represent the gene number overlap. Aside the plot is represented the color codes for each cancer tissue.
Mentions: To test whether the gene expression patterns that characterize Trp53ΔEC and RbΔEC; Trp53ΔEC mouse tumors (training dataset) are also present in human cancers with TP53 mutations and/or with poor clinical outcome, we performed an exhaustive comparison of the mouse tumor signature (682-probesets) with gene datasets of human cancer samples using the Oncomine human cancer genomics database (see Materials and Methods) [24,25]. First we analyzed the genes overexpressed in the mouse tumors (371 probesets), and compared them with the overexpressed genes in human samples bearing TP53 mutations. This meta-analysis showed a very significant overlap with many human epithelial and non-epithelial cancers, indicating that multiple genes overexpressed in the mouse epidermal tumors are in common with human tumors from distinct body sites and characterized by bearing mutant TP53 gene (Fig. 4a and Additional file 4). To study the existence of possible correlation with different types of p53 mutations in human tumors, we analyzed in further detail a breast cancer dataset containing gene expression and p53 mutation data of 247 patients [26], and which also showed the highest overlapping significance in the human p53-mutant tumors panel (asterisk in Fig. 4a) (98 overlapping genes, p-val = 1.6 × 10-66). As a measure of the status similarity with respect to mouse tumors, we calculated an overlapping score of each breast cancer sample (see Materials and Methods) and represented it as a function of TP53 mutational status. The mean differences and significance were calculated as the tumors were grouped by TP53 mutation status (mutant or wild type) or by mutation type (missense or truncating). As expected, the differences were highly significant between tumor samples bearing TP53 mutation or wild type (Fig. 4b, left panel), demonstrating that the mouse tumors expression profile could distinguish between both types of human tumors. Furthermore, the mean values were also significantly higher in the samples with truncating mutations when compared with missense mutations (Fig. 4b, right panel). Overall these analyses suggest that mouse tumors with somatic deficiency of both p53 alleles resemble human tumors with TP53 mutations, especially tumors that can produce truncated p53 proteins.

Bottom Line: 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.Remarkably, they are also enriched in human embryonic stem cell gene signatures, a characteristic feature of human aggressive tumors.Two of the genes of this signature, AURKA and UBE2C, were validated in human breast and cervical cancer as potential biomarkers of malignancy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Oncology Unit, Division of Biomedicine, CIEMAT, Ave, Complutense 22, E-28040 Madrid, Spain. ramon.garcia@ciemat.es

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus