ΔNp63 protein expression in uterine cervical and endometrial cancers

Lin, Zhenhua; Liu, Mingzhu; Li, Zhuhu; Kim, Changheon; Lee, Eung-Seok; Kim, Insun

doi:10.1007/s00432-006-0130-8

Cited by 30 publications

(31 citation statements)

References 17 publications

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“…By analysis of various p63 isoforms, a few authors did demonstrate an overexpression of DNp63 in different cancers [69,70]. The results of tumorigenicity assays indicate, that overexpression of DNp63 led to increased colony formation in vitro and increased tumor formation in nude mice [69], suggesting an oncogenic role of this transcript variant [22,69,70]. In contrast to these findings, a decreased TAp63 level was reported to be associated with poor clinical outcome in ductal and laryngeal squamous cell carcinomas [71,72].…”

Section: Discussionmentioning

confidence: 97%

“…On the other hand, Keyes et al showed no evidence of a predisposition to tumor growth in mice null for p63 [18]. Although there is an abundance of reports of p63 overexpression in many different tumors, above all in squamous cell carcinoma like head and neck cancer [19], lung cancers [20], cutaneous tumors [21], uterine tumors [22,23], and breast cancer [15,24,25], it seems to be clear that p63 is very rarely mutated in cancers [26].…”

Section: Introductionmentioning

confidence: 99%

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Clinical relevance of the putative stem cell marker p63 in breast cancer

Hanker

Karn

Ruckhaeberle

et al. 2009

Breast Cancer Res Treat

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P63 is a member of the p53 family. This protein is crucial for the maintenance of a stem cell population in the human epithelium and necessary for the normal development of all epithelial tissues including mammary glands. In normal breast tissue, the p63 seems to be a specific myoepithelial cell marker. P63 expression has been described in highly aggressive ER negative basal-like breast tumors. The value of p63 expression in ER positive disease is less clear. The expression levels of p63 mRNA by Affymetrix microarray analysis in a combined cohort of 2,158 ER positive breast cancers and its prognostic and predictive impact were analyzed. Tumor samples containing large amounts of benign breast tissue, which will interfere with p63 measurement, were excluded prior to the analysis. Survival analysis revealed a better prognosis of ER positive breast cancer expressing p63 (n = 410; P \ 0.036). No correlation of p63 with standard parameters was observed. In a subgroup analysis, endocrinetreated patients with high p63 expression showed a better prognosis than low p63 expression (P = 0.06; n = 186). In untreated patients, this effect was less clear (n = 148; P = 0.5). P63 is a positive prognostic factor in endocrinetreated ER positive breast cancer and might influence responsiveness to endocrine treatment. Thus, p63 could be helpful as a predictive factor for endocrine therapy.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Clinical relevance of the putative stem cell marker p63 in breast cancer

Hanker

Karn

Ruckhaeberle

et al. 2009

Breast Cancer Res Treat

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“…The DNp63 isoforms possess dominant-inhibitory functions over the TA isoforms of the p53 family (TAp63, TAp73 and p53) that usually result in prosurvival and pro-proliferation activities (Parsa et al, 1999;Barbieri et al, 2005;Wu et al, 2005;Rocco et al, 2006). Overexpression of DNp63 has been frequently observed in squamous cell carcinoma and in some other epithelial tumors (Hibi et al, 2000;Senoo et al, 2001;Moll and Slade, 2004;Lin et al, 2006) and, beyond its dominant negative effect over the pro-apoptotic and growth-arresting functions of the TA isoforms, DNp63 was found to contribute to tumor progression by favoring angiogenesis and chemoresistance (Wu et al, 2005;Zangen et al, 2005;Lanza et al, 2006;Muller et al, 2006;Rocco et al, 2006) and by modulating cell adhesion processes (Carroll et al, 2006;Yang et al, 2006). Regardless of the HIPK2-mediated regulation of DNp63a in response to DOX, we observed that HIPK2 depletion results in an increased expression of DNp63a even in non-stressing conditions (Figure 3e and data not shown), suggesting that the tumorassociated HIPK2 inactivation might contribute to DNp63a overexpression.…”

Section: Discussionmentioning

confidence: 99%

HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage

Lazzari¹,

Prodosmo²,

Siepi³

et al. 2011

Oncogene

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Homeodomain-interacting protein kinase 2 (HIPK2) is an emerging player in cell response to genotoxic agents that senses damage intensity and contributes to the cell's choice between cell cycle arrest and apoptosis. Phosphorylation of p53 at S46, an apoptosis-specific p53 posttranslational modification, is the most characterized HIPK2 function in response to lethal doses of ultraviolet (UV), ionizing radiation or different anticancer drugs, such as cisplatin, roscovitine and doxorubicin (DOX). Indeed, like p53, HIPK2 has been shown to contribute to the effectiveness of these treatments. Interestingly, p53-independent mechanisms of HIPK2-induced apoptosis were described for UV and tumor growth factor-b treatments; however, it is unknown whether these mechanisms are relevant for the responses to anticancer drugs. Because of the importance of the so-called 'p53-independent apoptosis and drug response' in human cancer chemotherapy, we asked whether p53-independent factor(s) might be involved in HIPK2-mediated chemosensitivity. Here, we show that HIPK2 depletion by RNA interference induces resistance to different anticancer drugs even in p53-null cells, suggesting the involvement of HIPK2 targets other than p53 in response to chemotherapy. In particular, we found that HIPK2 phosphorylates and promotes proteasomal degradation of DNp63a, a prosurvival DN isoform of the p53 family member, p63. Indeed, effective cell response to different genotoxic agents was shown to require phosphorylation-induced proteasomal degradation of DNp63a. In DOX-treated cells, we show that HIPK2 depletion interferes with DNp63a degradation, and expression of a HIPK2-resistant DNp63a-D390 mutant induces chemoresistance. We identify T397 as the DNp63a residue phosphorylated by HIPK2, and show that the nonphosphorylatable DNp63a-T397A mutant is not degraded in the face of either HIPK2 overexpression or DOX treatment. These results indicate DNp63a as a novel target of HIPK2 in response to genotoxic drugs.

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“…In fact, p63 has been shown to be overexpressed in many tumors, especially in squamous cell lung carcinoma (SCC) of the head and neck (HNSCC), lung [22], skin [29], and cervix [30,31]. Many of them actually overexpress the ΔNp63 isoforms, while TAp63 expression is lost [19,20,32].…”

Section: P63 In Human Diseasementioning

confidence: 99%

p40: A p63 Isoform Useful for Lung Cancer Diagnosis – A Review of the Physiological and Pathological Role of p63

2012

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At present, p63, TTF-1, and Napsin-A are the main immunochemical markers used to distinguish squamous cell carcinoma (SCC) from lung adenocarcinoma (ADC). However, studies using antibodies against p63 have demonstrated false-positive results with positivity in some ADC. In contrast, the expression of one of the p63 isoforms (ΔNp63), detected by the antibody p40, is highly specific for SCC. Since most cases of lung cancer are diagnosed in small specimens (cytology/biopsies) and saving material for molecular analysis is mandatory, we recommended the use of p40 (in adjunct with TTF-1 and/or Napsin-A) as the best approach to discriminate SCC and lung ADC. In this paper, we review the physiological and pathological role of p63 isoforms as well as their use as diagnostic markers in lung SCC.

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ΔNp63 protein expression in uterine cervical and endometrial cancers

Abstract: Immunohistochemical staining for DeltaNp63 is a powerful marker for squamous differentiation and useful in exclusion of glandular and neuroendocrine differentiation in uterine cervical cancers, but not always in endometrial cancers.

Cited by 30 publications

References 17 publications

Clinical relevance of the putative stem cell marker p63 in breast cancer

Clinical relevance of the putative stem cell marker p63 in breast cancer

HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage

p40: A p63 Isoform Useful for Lung Cancer Diagnosis – A Review of the Physiological and Pathological Role of p63

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