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• W2005013681 abstract "p63 and p73 are functionally and structurally related to the tumor suppressor p53. However, their own role in tumor suppression is unclear. Given the p53-like properties of p63 and p73, we tested whether they are involved in tumor suppression by aging mice heterozygous for mutations in all p53 family genes and scored for spontaneous tumors. We show here that p63+/−;p73+/− mice develop spontaneous tumors. Loss of p63 and p73 can also cooperate with loss of p53 in tumor development. Mice heterozygous for mutations in both p53 and p63 or p53 and p73 displayed higher tumor burden and metastasis compared to p53+/− mice. These findings provide evidence for a broader role for the p53 family than has been previously reported. p63 and p73 are functionally and structurally related to the tumor suppressor p53. However, their own role in tumor suppression is unclear. Given the p53-like properties of p63 and p73, we tested whether they are involved in tumor suppression by aging mice heterozygous for mutations in all p53 family genes and scored for spontaneous tumors. We show here that p63+/−;p73+/− mice develop spontaneous tumors. Loss of p63 and p73 can also cooperate with loss of p53 in tumor development. Mice heterozygous for mutations in both p53 and p63 or p53 and p73 displayed higher tumor burden and metastasis compared to p53+/− mice. These findings provide evidence for a broader role for the p53 family than has been previously reported. The discovery of the p53-related genes p63 and p73 raised the possibility that they may be cancer-associated genes. However, initial reports indicated that mutations in p63 and p73 are rare in human cancers. We have found that mice that are p63+/−;p73+/− develop malignant tumors at high frequency. In addition, p53+/−;p63+/− and p53+/−;p73+/− developed a more severe phenotype (higher tumor burden and metastases). Using mouse models, we have shown that inactivation of p63 and p73 leads to tumor types in the mouse frequently found to lose expression or have mutations in p63 or p73 in human tumors. This study identifies a previously unrecognized function of these genes and supports a broader role for the p53 family in tumor suppression. p63 and p73 were cloned due to their structural similarity to p53. However, they have been found to be more complex than p53 due to the existence of several variant isoforms. Both p63 and p73 contain carboxy-terminal spliced variants known as the TA isoforms. So-called ΔN variants also exist that lack the transactivation domain and are transcribed from an internal promoter within exon 3 of the full-length genes (Irwin and Kaelin, 2001Irwin M.S. Kaelin Jr., W.G. Role of the newer p53 family proteins in malignancy.Apoptosis. 2001; 6: 17-29Crossref PubMed Scopus (71) Google Scholar, Yang et al., 1998Yang A. Kaghad M. Wang Y. Gillett E. Fleming M.D. Dotsch V. Andrews N.C. Caput D. McKeon F. p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.Mol. Cell. 1998; 2: 305-316Abstract Full Text Full Text PDF PubMed Scopus (1767) Google Scholar). These different isoforms have been shown to have vastly different activities. The TA isoforms act similarly to p53. They have the ability to transactivate p53 target genes and induce apoptosis. In contrast, the ΔN isoforms have little transactivation activity and are thought to play a role in blocking transactivation of target genes of both p53 and their respective TA isoforms (Yang et al., 2002Yang A. Kaghad M. Caput D. McKeon F. On the shoulders of giants: p63, p73 and the rise of p53.Trends Genet. 2002; 18: 90-95Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar). Therefore, the TA isoforms might be expected to have a role in tumor suppression, while increased expression of the ΔN isoforms might be oncogenic. Gene targeting studies in the mouse have revealed that both p63 and p73 have roles in normal development (Mills et al., 1999Mills A.A. Zheng B. Wang X.J. Vogel H. Roop D.R. Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis.Nature. 1999; 398: 708-713Crossref PubMed Scopus (1632) Google Scholar, Yang et al., 1999Yang A. Schweitzer R. Sun D. Kaghad M. Walker N. Bronson R.T. Tabin C. Sharpe A. Caput D. Crum C. McKeon F. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.Nature. 1999; 398: 714-718Crossref PubMed Scopus (1825) Google Scholar, Yang et al., 2000Yang A. Walker N. Bronson R. Kaghad M. Oosterwegel M. Bonnin J. Vagner C. Bonnet H. Dikkes P. Sharpe A. et al.p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours.Nature. 2000; 404: 99-103Crossref PubMed Scopus (851) Google Scholar). The mutations delete the central DNA binding domain of p63 and p73 and, thus, affect all isoforms of the genes. p63-deficient mice are born with craniofacial abnormalities, limb truncations, and a thin layer of undifferentiated skin. They die within hours after birth due to desiccation and maternal neglect (Mills et al., 1999Mills A.A. Zheng B. Wang X.J. Vogel H. Roop D.R. Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis.Nature. 1999; 398: 708-713Crossref PubMed Scopus (1632) Google Scholar, Yang et al., 1999Yang A. Schweitzer R. Sun D. Kaghad M. Walker N. Bronson R.T. Tabin C. Sharpe A. Caput D. Crum C. McKeon F. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.Nature. 1999; 398: 714-718Crossref PubMed Scopus (1825) Google Scholar). p73 mutant mice also survive to birth but are runted and have hydrocephalus as well as hippocampal dysgenesis. The majority of p73-deficient mice live to be only 4 to 6 weeks old and die due to chronic infections (Yang et al., 2000Yang A. Walker N. Bronson R. Kaghad M. Oosterwegel M. Bonnin J. Vagner C. Bonnet H. Dikkes P. Sharpe A. et al.p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours.Nature. 2000; 404: 99-103Crossref PubMed Scopus (851) Google Scholar). In our colony, approximately 25% survive to adulthood. Because of the complexity of the p63 and p73 loci and the lack of a detailed characterization of the molecular effects of the targeted mutations, it is possible that the mutant alleles might still produce truncated mRNAs and proteins that could complicate the interpretation of the mutant phenotypes. The literature on p63 and p73 is complex and controversial, and their role in tumor suppression has been much debated. In studies performed to date, only a small percentage of human tumors have been shown to harbor p63 and p73 mutations (Irwin and Kaelin, 2001Irwin M.S. Kaelin Jr., W.G. Role of the newer p53 family proteins in malignancy.Apoptosis. 2001; 6: 17-29Crossref PubMed Scopus (71) Google Scholar). However, recent studies have shown that p63 and p73 have tumor-suppressive activities in human tumors. While some studies have shown overexpression of some isoforms of p63 or p73 in human tumors (Hibi et al., 2000Hibi K. Trink B. Patturajan M. Westra W.H. Caballero O.L. Hill D.E. Ratovitski E.A. Jen J. Sidransky D. AIS is an oncogene amplified in squamous cell carcinoma.Proc. Natl. Acad. Sci. USA. 2000; 97: 5462-5467Crossref PubMed Scopus (428) Google Scholar, Nozaki et al., 2001Nozaki M. Tada M. Kashiwazaki H. Hamou M.F. Diserens A.C. Shinohe Y. Sawamura Y. Iwasaki Y. de Tribolet N. Hegi M.E. p73 is not mutated in meningiomas as determined with a functional yeast assay but p73 expression increases with tumor grade.Brain Pathol. 2001; 11: 296-305Crossref PubMed Scopus (31) Google Scholar), certain tumor types (transitional cell carcinomas, mammary adenocarcinomas, squamous cell carcinomas, and osteosarcomas) exhibit loss or reduced expression of p63 and/or p73 (Ahomadegbe et al., 2000Ahomadegbe J.C. Tourpin S. Kaghad M. Zelek L. Vayssade M. Mathieu M.C. Rochard F. Spielmann M. Tursz T. Caput D. et al.Loss of heterozygosity, allele silencing and decreased expression of p73 gene in breast cancers: Prevalence of alterations in inflammatory breast cancers.Oncogene. 2000; 19: 5413-5418Crossref PubMed Scopus (40) Google Scholar, Koga et al., 2003Koga F. Kawakami S. Fujii Y. Saito K. Ohtsuka Y. Iwai A. Ando N. Takizawa T. Kageyama Y. Kihara K. Impaired p63 expression associates with poor prognosis and uroplakin III expression in invasive urothelial carcinoma of the bladder.Clin. Cancer Res. 2003; 9: 5501-5507PubMed Google Scholar, Park et al., 2000Park B.J. Lee S.J. Kim J.I. Lee C.H. Chang S.G. Park J.H. Chi S.G. Frequent alteration of p63 expression in human primary bladder carcinomas.Cancer Res. 2000; 60: 3370-3374PubMed Google Scholar, Park et al., 2004Park H.R. Kim Y.W. Park J.H. Maeng Y.H. Nojima T. Hashimoto H. Park Y.K. Low expression of p63 and p73 in osteosarcoma.Tumori. 2004; 90: 239-243PubMed Google Scholar, Puig et al., 2003Puig P. Capodieci P. Drobnjak M. Verbel D. Prives C. Cordon-Cardo C. Di Como C.J. p73 Expression in human normal and tumor tissues: Loss of p73α expression is associated with tumor progression in bladder cancer.Clin. Cancer Res. 2003; 9: 5642-5651PubMed Google Scholar, Urist et al., 2002Urist M.J. Di Como C.J. Lu M.L. Charytonowicz E. Verbel D. Crum C.P. Ince T.A. McKeon F.D. Cordon-Cardo C. Loss of p63 expression is associated with tumor progression in bladder cancer.Am. J. Pathol. 2002; 161: 1199-1206Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). However, these studies have been complicated by the lack of antibodies that distinguish between the TA and ΔN isoforms. More recent studies using antibodies or RT-PCR for specific isoforms of p63 or p73 have shown increased or decreased expression of the TA or ΔN isoforms of p63 and p73. The few studies on human tumors that have been performed to date to determine the significance of the TA versus ΔN isoforms have shown that some tumors do specifically lose TA isoform expression (Park et al., 2000Park B.J. Lee S.J. Kim J.I. Lee C.H. Chang S.G. Park J.H. Chi S.G. Frequent alteration of p63 expression in human primary bladder carcinomas.Cancer Res. 2000; 60: 3370-3374PubMed Google Scholar), while others have increased expression of the ΔN isoforms (Concin et al., 2004Concin N. Becker K. Slade N. Erster S. Mueller-Holzner E. Ulmer H. Daxenbichler G. Zeimet A. Zeillinger R. Marth C. Moll U.M. Transdominant ΔTAp73 isoforms are frequently up-regulated in ovarian cancer. Evidence for their role as epigenetic p53 inhibitors in vivo.Cancer Res. 2004; 64: 2449-2460Crossref PubMed Scopus (126) Google Scholar, Moll, 2003Moll U.M. The role of p63 and p73 in tumor formation and progression: Coming of age toward clinical usefulness.Clin. Cancer Res. 2003; 9: 5437-5441PubMed Google Scholar, Zaika et al., 2002Zaika A.I. Slade N. Erster S.H. Sansome C. Joseph T.W. Pearl M. Chalas E. Moll U.M. DeltaNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors.J. Exp. Med. 2002; 196: 765-780Crossref PubMed Scopus (293) Google Scholar). In addition to loss of expression of p63 in some human tumors, 12% of chronic myelogenous leukemias examined were found to have mutations in p63 (Yamaguchi et al., 2001Yamaguchi H. Inokuchi K. Sakuma Y. Dan K. Mutation of the p51/p63 gene is associated with blastic crisis in chronic myelogenous leukemia.Leukemia. 2001; 15: 1729-1734Crossref PubMed Scopus (26) Google Scholar) contributing to the evidence that p63 has tumor-suppressive activities. Many more studies using antibodies or RT-PCR for specific isoforms must be performed in additional human tumors to determine the significance of the loss or gain of each isoform. To date, a systematic analysis of tumor development in mice that are mutant for p63 and p73 has not been performed, and the synergistic effects of the p53 family in tumor suppression have not been examined. The present study examines the long-term tumorigenic effects of p63 and p73 mutation, alone or in combination with p53. The data support a model whereby p63 and p73 play an important role in tumor suppression in specific tissues in the mouse. The p63 and p73 mutant mice used in this study carry mutations that remove a large segment of the central DNA binding domain that are thought to inactivate all of the isoforms of these genes (Mills et al., 1999Mills A.A. Zheng B. Wang X.J. Vogel H. Roop D.R. Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis.Nature. 1999; 398: 708-713Crossref PubMed Scopus (1632) Google Scholar, Yang et al., 1999Yang A. Schweitzer R. Sun D. Kaghad M. Walker N. Bronson R.T. Tabin C. Sharpe A. Caput D. Crum C. McKeon F. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.Nature. 1999; 398: 714-718Crossref PubMed Scopus (1825) Google Scholar, Yang et al., 2000Yang A. Walker N. Bronson R. Kaghad M. Oosterwegel M. Bonnin J. Vagner C. Bonnet H. Dikkes P. Sharpe A. et al.p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours.Nature. 2000; 404: 99-103Crossref PubMed Scopus (851) Google Scholar). Due to the complexity of these loci, it remains possible the mutant alleles produce truncated products; however, for simplicity, we have referred to the mutant alleles here as p63−/− and p73−/−. To determine if p63 or p73 mutation alone could cause tumor predisposition, a large cohort of p63 and p73 heterozygous mice (p63+/− and p73+/−) were aged for two years or until moribund. Both groups (consisting of 40 mice) for each genotype had a shortened life span compared to their wild-type littermates (Figure 1). By 14 to 15 months of age, half of the p63+/− and p73+/− mice were moribund and had to be euthanized. Statistical analysis was performed using a log-rank test. The survival time of p63+/− and p73+/− mice was found to be statistically significant compared to the time of survival of wild-type mice, with a p value of 0.0001 for both. After two years, 32 out of 40 p63+/− mice and 36 out of 40 p73+/− mice had been sacrificed or died, compared to 8 out of 40 in the wild-type group. All animals in this study were subjected to full necropsy to determine the frequency and spectrum of spontaneous tumor formation. Strikingly, p63+/− and p73+/− mice developed malignant lesions, demonstrating that these genes can act as tumor suppressors. Ten percent of p63+/− mice (n = 40 total mice examined) developed squamous cell carcinomas, and 20% developed histiocytic sarcomas by 12 months of age (Table 1). Ten percent of p73+/− mice developed lung adenocarcinomas, while 12.5% percent developed thymic lymphoma and 12.5% had hemangiosarcomas (Table 1). In addition to these malignant lesions, heterozygous mutant mice showed an increase in benign premalignant lesions, such as squamous cell hyperplasia and multiple lung adenomas. The frequency of lung adenomas in p63+/− and p73+/− was 2.5 and 4 times that seen in wild-type mice, respectively (Table 1). While not all of the mice developed malignant lesions, the remaining mice died from complications due to the benign lesions. For example, in p63+/− and p73+/− mice, many died due to obstructed airways from hyperplastic or premalignant lesions in the pharynx, larynx, mouth, or tongue. In addition to analyzing heterozygous mice for p73, a group of 40 p73−/− mice were aged until moribund. As reported previously, many of them died due to chronic infections at approximately 4 to 5 weeks of age (Yang et al., 2000Yang A. Walker N. Bronson R. Kaghad M. Oosterwegel M. Bonnin J. Vagner C. Bonnet H. Dikkes P. Sharpe A. et al.p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours.Nature. 2000; 404: 99-103Crossref PubMed Scopus (851) Google Scholar). We were able to monitor 10 out of 40 to the age of 10 months. Six out of those 10 developed lung adenocarcinomas, indicating that loss of p73 in this tissue leads to tumor formation (Table 1).Table 1Tumor spectrum of mice mutant for the p53 family membersTumor typeGenotype% mice (n = 40)Tumor typeGenotype% mice (n = 40)Mammary adenocarcinomawild-type0%Osteosarcomap73+/−0%p53+/−0%p53+/−p63+/−20%p63+/−0%p53+/−;p73+/−20%p73+/−0%p63+/−;p73+/−20%p53+/−;p63+/−10%Hepatocellular carcinomawild-type0%p53+/−;p73+/−0%p53+/−0%p63+/−;p73+/−20%p63+/−0%Lung adenomawild-type10%p73+/−0%p53+/−0%p53+/−;p63+/−0%p63+/−25%p53+/−;p73+/−15%p73+/−40%p63+/−;p73+/−0%p53+/−;p63+/−0%Transitional cell carcinomawild-type0%p53+/−;p73+/−0%p53+/−0%p63+/−;p73+/−0%p63+/−0%Lung adenocarcinomawild-type0%p73+/−0%p53+/−0%p53+/−;p63+/−20%p63+/−0%p53+/−;p73+/−0%p73+/−10%p63+/−;p73+/−0%p53+/−;p63+/−0%Myelogenous leukemiawild-type0%p53+/−;p73+/−10%p53+/−0%p63+/−;p73+/−15%p63+/−0%*p73−/−60% (n = 10 mice)p73+/−0%Salivary adenomawild-type0%p53+/−;p63+/−15%p53+/−0%p53+/−;p73+/−0%p63+/−0%p63+/−;p73+/−10%p73+/−0%Thymic lymphomawild-type0%p53+/−;p63+/−0%p53+/−20%p53+/−;p73+/−0%p63+/−0%p63+/−;p73+/−25%p73+/−12.5%Squamous cell hyperplasiawild-type5%p53+/−;p63+/−10%p53+/−0%p53+/−;p73+/−22.5%p63+/−50%p63+/−;p73+/−10%p73+/−30%Histiocytic sarcomawild-type0%p53+/−;p63+/−0%p53+/−22.5%p53+/−;p73+/−0%p63+/−20%p63+/−;p73+/−20%p73+/−0%Squamous cell carcinomawild-type0%p53+/−;p63+/−0%p53+/−0%p53+/−;p73+/−0%p63+/−10%p63+/−;p73+/−0%p73+/−0%Hemangiosarcomawild-type0%p53+/−;p63+/−50%p53+/−15%p53+/−;p73+/−0%p63+/−0%p63+/−;p73+/−30%p73+/−12.5%Acinar pancreatic carcinomawild-type0%p53+/−;p63+/−0%p53+/−0%p53+/−;p73+/−10%p63+/−0%p63+/−;p73+/−5%p73+/−0%Rhabdomyosarcomawild-type0%p53+/−;p63+/−0%p53+/−20%p53+/−;p73+/−15%p63+/−0%p63+/−;p73+/−0%p73+/−0%Osteosarcomawild-type0%p53+/−;p63+/−20%p53+/−22.5%p53+/−;p73+/−20%p63+/−0%p63+/−;p73+/−20% Open table in a new tab LOH is one of the hallmarks of tumor suppressor gene inactivation in cancer (Knudson, 1975Knudson Jr., A.G. Genetics of human cancer.Genetics. 1975; 79: 305-316PubMed Google Scholar, Knudson, 1986Knudson Jr., A.G. Genetics of human cancer.Annu. Rev. Genet. 1986; 20: 231-251Crossref PubMed Scopus (309) Google Scholar). To determine if the tumors in the p63+/− or p73+/− mice lose the wild-type allele of the respective genes, DNA was extracted from tumors that were macroscopically visible, and analyzed by Southern blotting. Microscopic tumors were analyzed using laser capture microdissection followed by PCR. As shown in Table 2, a high percentage of tumors in the p63+/− and p73+/− mice exhibited loss of the remaining wild-type allele (see Table 2 for full summary of LOH data). For example, in all 5 of the squamous cell carcinomas (SCC) (Figure 2B [T7]) and 7 of the 10 histiocytic sarcomas from p63+/− mice, loss of the wild-type copy of p63 was observed (Table 2). Likewise, 8 of 10 thymic lymphomas and 4 of 5 lung adenocarcinomas and hemangiosarcomas in p73+/− tumors exhibited LOH (Table 2 and Figure 2D [T10]). These data strongly support the tumor suppressive functions of p63 and p73 and establish a tumor cell autonomous effect for their mutation in tumor development.Table 2Tumors derived from mice mutant for the p53 family of genes exhibit LOHGenotypeTumorp53p63p73Combinedp53+/−thymic lymphoma, n = 1090%N/AN/AN/Ahistiocytic sarcoma, n = 580%N/AN/AN/Arhabdomyosarcoma, n = 580%N/AN/AN/Aosteosarcoma, n = 580%N/AN/AN/Ahemangiosarcoma, n = 580%N/AN/AN/Ap63+/−histicytic sarcoma, n = 10N/A70%N/AN/Asquamous cell carcinoma, n = 5N/A100%N/AN/Alung adenoma, n = 5N/A60%N/AN/Ap73+/−thymic lymphoma, n = 10N/AN/A80%N/Alung adenoma, n = 5N/AN/A100%N/Alung adenocarcinoma, n = 5N/AN/A80%N/Ahemangiosarcoma, n = 5N/AN/A80%N/Ap53+/−;p63+/−transitional cell carcinoma, n = 2040%80%N/A40%mammary adenocarcinoma, n = 200%80%N/A0%squamous cell carcinoma, n = 100%100%N/A0%thymic lymphoma, n = 1090%70%N/A70%rhabdomyosarcoma, n = 1080%50%N/A40%osteosarcoma, n = 1080%60%N/A40%myelogenous leukemia, n = 580%100%N/A80%p53+/−;p73+/−thymic lymphoma, n = 1090%N/A80%80%hepatocellular carcinoma, n = 100%N/A90%0%acinar pancreatic carcinoma, n = 100%N/A90%0%rhabdomyosarcoma, n = 580%N/A20%20%osteosarcoma, n = 1080%N/A70%50%p63+/−;p73+/−mammary adenocarcinoma, n = 10N/A90%90%90%lung adenocarcinoma, n = 10N/A80%90%80%thymic lymphoma, n = 10N/A70%80%70%squamous cell carcinoma, n = 15N/A100%0%0%myelogenous leukemia, n = 4N/A100%50%50%N/A, not applicable; LOH, loss of heterozygosity; n, number of tumors analyzed; %, tumors with LOH. Open table in a new tab N/A, not applicable; LOH, loss of heterozygosity; n, number of tumors analyzed; %, tumors with LOH. To examine whether p63 and p73 might have overlapping functions related to tumor suppression, we intercrossed mice heterozygous for p63 and p73 to obtain mice that were heterozygous for mutations in both genes (p63+/−;p73+/−) (n = 40 mice). In a two-year aging study, these mice were found to have a shorter life span than wild-type, p63+/−, or p73+/− mice (Figure 1). The median survival age for these compound heterozygotes was 8 months, which is similar to the median survival age of p53+/− mice (10 months), compared to 14 and 15 months for p73+/− and p63+/− mice, respectively (Figure 1). Statistical analysis using a log-rank test revealed that the difference in the median survival age between the p63+/−;p73+/− mice and the p63 and p73 single heterozygotes is statistically significant (p = 0.0001). p63+/−;p73+/− mice that died by 6 months of age had developed thymic lymphoma, hemangiosarcoma, or myelogenous leukemia (Figure 3C ). For mice that died between 6 and 12 months of age, carcinomas were most prevalent: mammary adenocarcinomas, lung adenocarcinomas, and squamous cell carcinomas (Table 1 and Figures 3A, 3B, and 3D). Many of these tumor types (including myelogenous leukemia, lung adenocarcinomas, squamous cell carcinomas, and mammary adenocarcinomas) were not detected in the p53+/− mice (Table 1), suggesting different sites of action for p63 and p73 in tumor suppression. Strikingly, the tumor types detected in the mice are precisely those that have been shown to lose expression of p63 and/or p73 in human tumors. These include transitional cell carcinomas of the bladder (Koga et al., 2003Koga F. Kawakami S. Fujii Y. Saito K. Ohtsuka Y. Iwai A. Ando N. Takizawa T. Kageyama Y. Kihara K. Impaired p63 expression associates with poor prognosis and uroplakin III expression in invasive urothelial carcinoma of the bladder.Clin. Cancer Res. 2003; 9: 5501-5507PubMed Google Scholar, Park et al., 2000Park B.J. Lee S.J. Kim J.I. Lee C.H. Chang S.G. Park J.H. Chi S.G. Frequent alteration of p63 expression in human primary bladder carcinomas.Cancer Res. 2000; 60: 3370-3374PubMed Google Scholar, Puig et al., 2003Puig P. Capodieci P. Drobnjak M. Verbel D. Prives C. Cordon-Cardo C. Di Como C.J. p73 Expression in human normal and tumor tissues: Loss of p73α expression is associated with tumor progression in bladder cancer.Clin. Cancer Res. 2003; 9: 5642-5651PubMed Google Scholar, Urist et al., 2002Urist M.J. Di Como C.J. Lu M.L. Charytonowicz E. Verbel D. Crum C.P. Ince T.A. McKeon F.D. Cordon-Cardo C. Loss of p63 expression is associated with tumor progression in bladder cancer.Am. J. Pathol. 2002; 161: 1199-1206Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar), mammary adenocarcinomas (Ahomadegbe et al., 2000Ahomadegbe J.C. Tourpin S. Kaghad M. Zelek L. Vayssade M. Mathieu M.C. Rochard F. Spielmann M. Tursz T. Caput D. et al.Loss of heterozygosity, allele silencing and decreased expression of p73 gene in breast cancers: Prevalence of alterations in inflammatory breast cancers.Oncogene. 2000; 19: 5413-5418Crossref PubMed Scopus (40) Google Scholar, Wang et al., 2002Wang X. Mori I. Tang W. Nakamura M. Nakamura Y. Sato M. Sakurai T. Kakudo K. p63 expression in normal, hyperplastic and malignant breast tissues.Breast Cancer. 2002; 9: 216-219Crossref PubMed Scopus (64) Google Scholar, Yamamoto et al., 2002Yamamoto T. Oda K. Kubota T. Miyazaki K. Takenouti Y. Nimura Y. Hamaguchi M. Matsuda S. Expression of p73 gene, cell proliferation and apoptosis in breast cancer: Immunohistochemical and clinicopathological study.Oncol. Rep. 2002; 9: 729-735PubMed Google Scholar), osteosarcomas (Park et al., 2004Park H.R. Kim Y.W. Park J.H. Maeng Y.H. Nojima T. Hashimoto H. Park Y.K. Low expression of p63 and p73 in osteosarcoma.Tumori. 2004; 90: 239-243PubMed Google Scholar), and myelogenous leukemia (Inokuchi et al., 2001Inokuchi K. Hamaguchi H. Taniwaki M. Yamaguchi H. Tanosaki S. Dan K. Establishment of a cell line with AML1–MTG8, TP53, and TP73 abnormalities from acute myelogenous leukemia.Genes Chromosomes Cancer. 2001; 32: 182-187Crossref PubMed Scopus (6) Google Scholar, Yamaguchi et al., 2001Yamaguchi H. Inokuchi K. Sakuma Y. Dan K. Mutation of the p51/p63 gene is associated with blastic crisis in chronic myelogenous leukemia.Leukemia. 2001; 15: 1729-1734Crossref PubMed Scopus (26) Google Scholar). In fact, a mutation in p63 and abnormalities in p73 that are associated with myelogenous leukemia have been found (Inokuchi et al., 2001Inokuchi K. Hamaguchi H. Taniwaki M. Yamaguchi H. Tanosaki S. Dan K. Establishment of a cell line with AML1–MTG8, TP53, and TP73 abnormalities from acute myelogenous leukemia.Genes Chromosomes Cancer. 2001; 32: 182-187Crossref PubMed Scopus (6) Google Scholar, Yamaguchi et al., 2001Yamaguchi H. Inokuchi K. Sakuma Y. Dan K. Mutation of the p51/p63 gene is associated with blastic crisis in chronic myelogenous leukemia.Leukemia. 2001; 15: 1729-1734Crossref PubMed Scopus (26) Google Scholar). Interestingly, 10% of p63+/−;p73+/− mice develop myelogenous leukemia, providing a suitable mouse model in which to study the disease. In addition to malignant lesions, some p63+/−;p73+/− mice also developed benign or borderline malignant lesions, including lung adenomas, salivary adenomas, and squamous cell hyperplasia of various grades (Table 1). The tumors from p63+/−;p73+/− mice exhibited loss of either wild-type p63 or p73 or, in many cases, both genes. For example, in 9 of 10 mammary adenocarcinomas from these mice, loss of both p63 and p73 was detected (Table 2 and Figures 2B and 2D [T11]). A similar pattern was observed for lung adenocarcinomas and thymic lymphomas (Table 2). Additionally, half of the myelogenous leukemia cases in p63+/−;p73+/− mice lost both p63 and p73. In contrast, all 15 of the squamous cell carcinomas assayed from p63+/−;p73+/− mice selectively lost the wild-type allele of p63 (Table 2). Thus, p63 and p73 participate in tumor suppression in tissues distinct from that of p53, and the combination of the loss of p63 and p73 accelerates tumorigenesis. It was striking that some of the prevalent tumor types detected in the double mutant mice were mammary adenocarcinomas and myelogenous leukemia. These are the tumor types in humans that show loss or downregulation of p63 and/or p73 (Ahomadegbe et al., 2000Ahomadegbe J.C. Tourpin S. Kaghad M. Zelek L. Vayssade M. Mathieu M.C. Rochard F. Spielmann M. Tursz T. Caput D. et al.Loss of heterozygosity, allele silencing and decreased expression of p73 gene in breast cancers: Prevalence of alterations in inflammatory breast cancers.Oncogene. 2000; 19: 5413-5418Crossref PubMed Scopus (40) Google Scholar, Inokuchi et al., 2001Inokuchi K. Hamaguchi H. Taniwaki M. Yamaguchi H. Tanosaki S. Dan K. Establishment of a cell line with AML1–MTG8, TP53, and TP73 abnormalities from acute myelogenous leukemia.Genes Chromosomes Cancer. 2001; 32: 182-187Crossref PubMed Scopus (6) Google Scholar, Moll, 2003Moll U.M. The role of p63 and p73 in tumor formation and progression: Coming of age toward clinical usefulness.Clin. Cancer Res. 2003; 9: 5437-5441PubMed Google Scholar, Park et al., 2000Park B.J. Lee S.J. Kim J.I. Lee C.H. Chang S.G. Park J.H. Chi S.G. Frequent alteration of p63 expression in human primary bladder carcinomas.Cancer Res. 2000; 60: 3370-3374PubMed Google Scholar, Park et al., 2004Park H.R. Kim Y.W. Park J.H. Maeng Y.H. Nojima T. Hashimoto H. Park Y.K. Low expression of p63 and p73 in osteosarcoma.Tumori. 2004; 90: 239-243PubMed Google Scholar, Puig et al., 2003Puig P. Capodieci P. Drobnjak M. Verbel D. Prives C. Cordon-Cardo C. Di Como C.J. p73 Expression in human normal and tumor tissues: Loss of p73α expression is associated with tumor progression in bladder cancer.Clin. Cancer Res. 2003; 9: 5642-5651PubMed Google Scholar, Urist et al., 2002Urist M.J. Di Como C.J. Lu M.L. Charytonowicz E. Verbel D. Crum C.P. Ince T.A. McKeon F.D. Cordon-Cardo C. Loss of p63 expression is associated with tumor progression in bladder cancer.Am. J. Pathol. 2002; 161: 1199-1206Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, Wang et al., 2002Wang X. Mori I. Tang W. Nakamura M. Nakamura Y. Sato M. Sakurai T. Kakudo K. p63 expression in normal, hyperplastic and malignant breast tissues.Breast Cancer. 2002; 9: 216-219Crossref PubMed Scopus (64) Google Scholar, Yamaguchi et al., 2001Yamaguchi H. Inokuchi K. Sakuma Y. Dan K. Mutation of the p51/p63 gene is associated with blastic crisis in chronic myelogenous leukemia.Leukemia. 2001; 15: 1729-1734Crossref PubMed Scopus (26) Google Scholar, Yamamoto et al., 2002Yamamoto T. Oda K. Kubota T. Miyazaki K. Takenouti Y. Nimura Y. Hamaguchi M. Matsuda S. Expression of p73 gene, cell proliferation and apoptosis in breast cancer: Immunohistochemical and clinicopathological study.Oncol. Rep. 2002; 9: 729-735PubMed Google Scholar). In fact, the study of human myelogenous leukemias identified a mutation in p63 associated with the blast crisis of the disease in 12% of cases analyzed, indicating again a correlation between the human and mouse data (Yamaguchi et al., 2001Yamaguchi H. Inokuchi K. Sakuma Y. Dan K. Mutation of the p51/p63 gene is associated with blastic crisis in chronic myelogenous leukemia.Leukemia. 2001; 15: 1729-1734Crossref PubMed Scopus (26) Google Sch" @default.
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