Role of P63 Amplification and Overexpression in Lung Cancer Development

Massion, Pierre P.; Taflan, Peter M.; Rahman, S.M. Jamshedur; Yıldız, Pınar; Shyr, Yu; Carbone, David P.; González, Adriana

doi:10.1378/chest.125.5_suppl.102s-a

Cited by 199 publications

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“…S100A2 has recently been reported to be a target of DNp63 (Hibi et al, 2003) a transcriptional activator. Overexpression of DNp63 in NSCLC has also been reported by Massion et al (2003), who also demonstrated that amplification of the p63 gene is an early event in lung cancer development. Interestingly, they also showed that p63 was strongly expressed in the basal cells of the normal bronchial epithelium.…”

Section: Discussionmentioning

confidence: 53%

S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell lung carcinomas

et al. 2004

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S100A2 gene products were shown to be frequently and dramatically over-represented in non-small cell lung cancer (NSCLC) lesions over normal tissue by microarray analysis. We have now analysed an independent series of NSCLC tumours and multiple matched normal bronchial epithelial sites by RT -PCR and immunohistochemistry to investigate: whether this expression pattern can be confirmed and whether elevated expression is associated with tumour histology, clinical outcome or preneoplasia. In this second series, S100A2 was strongly expressed in 76% (35 out of 46) of tumours, more frequently in squamous cell than adenocarcinomas (Po0.002). This strong expression was not related to high-level gene amplification, but was associated in one of five informative cases with an allele-specific imbalance in transcript levels. Most tumours strongly expressed the DNp63 transcript, the product of which is a putative regulator of S100A2 transcription and while all but one of the tumours positive for DNp63 expressed S100A2, others negative for this regulator also expressed the gene. Contrary to the hypothesis that S100A2 is a tumour suppressor, no somatic mutations were identified in the coding sequence in 44 tumours. Furthermore, an examination of multiple tumour-free epithelial sites from 20 patients showed that strong expression was often associated with increasing levels of disorder in preinvasive bronchial lesions (Po0.0001).

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Section: Discussionmentioning

confidence: 53%

S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell lung carcinomas

et al. 2004

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“…Therefore, it is conceivable that activation (or induction) of p63 may divert the intraductal neoplastic cells towards a more mature, metaplastic process. As in other organs, 3,9,[23][24][25] DNp63 is a reliable marker of squamous differentiation also in pancreatic carcinoma. Among invasive carcinomas of the pancreas, DNp63 immuno-expression is largely limited to the areas of squamous differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…4,6 The role of p63 in tumor progression or suppression seems to be far more limited. 2,4,5,[7][8][9][10][11][12] While the role of p63 in cellular pathways is not well understood, it has been suggested that it is the molecular switch for initiation of the epithelial stratification program. 13 Not only does the role, but the regulation of p63 also appear to be complex.…”

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confidence: 99%

“…As the key molecule of the epithelial stratification program, 13 DNp63 expression is highly specific for squamous differentiation in neoplasia, and is usually not detected in nonsquamous carcinomas such as adenocarcinoma, small cell carcinoma or mesothelioma and others. 3,9,21,[23][24][25][26] This is valuable in the differential diagnosis of poorly differentiated malignant tumors of undetermined origin.…”

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confidence: 99%

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DeltaNp63 expression in pancreas and pancreatic neoplasia

et al. 2005

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DeltaNp63 (DNp63) has become widely used, in particular, for distinguishing invasive carcinomas from noninvasive ducts by highlighting the myoepithelial or basal cells in the breast and prostate, respectively. It is not known whether this marker may have any application in another exocrine organ, the pancreas. As the ductal and intraductal proliferations of this organ become better characterized, the need for markers to distinguish among these processes increases. We investigated immunohistochemical expression of DNP63 in 105 cases. A total of 25 cases were non-neoplastic pancreata, 25 were pancreatic intraepithelial neoplasia (PanIN) of various grades, and 50 were examples of pancreatic ductal adenocarcinoma. Sections of non-neoplastic pancreata included various types of non-neoplastic processes such as squamous/transitional metaplasia (five cases), which can be mistaken for high-grade PanINs, as well as various degrees of reactive ductal atypia and incidental microcysts with attenuated lining (five cases). No DNp63 expression was noted in normal pancreatic ducts. On the other hand, all five foci of squamous/transitional metaplasia were strongly and uniformly positive for this marker. DNp63 labeling was also noted in those incidental microcysts lined by attenuated cells, seen amidst normal pancreatic lobules. All PanINs were negative. Among invasive carcinomas, DNp63 expression was detected only in areas of squamous differentiation and was completely absent in ordinary ductal areas. Based on this observation, five additional cases of adenosquamous/squamous carcinoma was retrieved and stained, and the squamous components of all of these were also positive. In conclusion, (I) DNp63 is a reliable marker of squamous differentiation in the pancreas. It is valuable in distinguishing squamous/transitional metaplasia from PanINs, a distinction of importance for both researchers and diagnosticians. Among invasive carcinomas, it seems to be entirely specific for areas of squamous differentiation. (II) Those incidental microcysts seen in acinar lobules and lined by attenuated cells are also positive for DNp63, which suggests that they may be metaplastic in nature, and that they do not represent neoplastic cells. (III) Unlike the ducts of other exocrine organs, breast and prostate, there are no DNp63-expressing cells in the normal pancreatic ducts, and therefore, this marker cannot be used in distinguishing invasive carcinomas from the non-invasive ducts. (IV) No p63-expressing 'stem' cells are present in the pancreas.

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“…Some p63 þ /À mice are cancer-prone 25 while other genetic background p63 þ /À mice show premature aging but no cancer. 26 In humans, the p63 gene can be frequently amplified in squamous cells in lung 27 and cervical carcinomas. 28 TAp63 proteins are expressed in the nuclei of a subpopulation of lymphoid cells and in most malignant lymphomas, whereas DNp63 proteins are not expressed.…”

Section: P63 and Cancermentioning

confidence: 99%

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

2006

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Abstractp63, p73 and p53 compose a family of transcription factors involved in cell response to stress and development. p53 is the most frequently mutated gene in cancer (50%) and loss of p53 activity is considered to be ubiquitous to all cancers. Recent publications may have a profound impact on our understanding of p53 tumour suppressor activity. p63, p73 and p53 genes have a dual gene structure conserved in drosophila, zebrafish and man. They encode for multiple p63, p73 or p53 proteins containing different protein domains (isoforms) due to multiple splicing, alternative promoter and alternative initiation of translation. In this review, we describe the different isoforms of p63, p73, p53 and their roles in development and cancer. The changes in the interactions between p53, p63 and p73 isoforms are likely to be fundamental to our understanding in the transition between normal cell cycling and the onset of tumour formation. Cell Death and Differentiation (2006) Introduction p53 was discovered in 1979 as a protein interacting with the oncogenic T antigen from SV40 virus. 1-5 p53 protein is the product of a pivotal tumor-suppressor gene whose inactivation by mutation or interaction with viral or overexpressed cellular proteins occurs in almost all cancers. 6 The p53 protein integrates multiple cellular stress signals assessing cellular damages to trigger either cell-cycle arrest or programmed cell death (apoptosis). 7 These effects are predominantly due to p53's ability to bind DNA through p53-responsive element (p53RE) 8,9 and regulate the transcription of genes involved in these processes, such as p21 10 (cell cycle arrest), Puma 11 or Scotin 12 (apoptosis). Thereby, p53 prevents proliferation of genetically abnormal cells and thus cancer formation.Two p53-related genes, p63 and p73, were identified in 1997. 13,14 The high level of sequence similarity between p63, p73 and p53 proteins, particularly in the DNA binding domain, allows p63 and p73 to transactivate p53-responsive genes causing cell cycle arrest and apoptosis. Therefore, p63, p73 and p53 genes form a family of transcription factor. However, they are not functionally entirely redundant and the primary role of each p53 family member -as determined by transgenetic knockout mice -illustrates that each protein has its own unique functions.We recently published that the p53 gene family has a dual gene structure conserved from drosophila to man. 15 Like most of the genes in the human genome, 16 p53 gene family members express multiple mRNA variants due to multiple splicing and alternative promoters. Hence, p53 gene family members express different forms of p53 protein containing different domain of the protein (isoforms). In this review, we will summarise the different isoforms of p63, p73 and p53 expressed in human, mouse and drosophila. p63The mouse p63 gene is composed of 15 exons spanning over 208 000 bp (GenBank Accession Number: AF533892) on chromosome 16, while the human p63 gene is composed of 15 exons, spanning over 270 000 bp on chromosome 3q2...

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Role of P63 Amplification and Overexpression in Lung Cancer Development

Cited by 199 publications

References 0 publications

S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell lung carcinomas

S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell lung carcinomas

DeltaNp63 expression in pancreas and pancreatic neoplasia

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

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