Allelic loss of p53 gene is associated with genesis and maintenance, but not invasion, of mouse carcinoma in situ of the bladder

Jin Cheng, Hongying Huang, Joanne Pak, Ellen Shapiro, Tung Tien Sun, Carlos Cordon-Cardo, Frederic M. Waldman, Xue Ru Wu

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Carcinoma in situ (CIS) of the bladder has recently been proposed to be a heterogeneous group of diseases with varied histogenesis and biological behavior. In this study, we describe the sequential steps of CIS development and progression in a transgenic mouse model expressing low levels of the SV40 large T antigen. We found that CIS in transgenic mice arose from urothelial dysplasia, that CIS could persist for an extended period of time without invasion, and that the majority of CIS eventually evolved into high-grade, superficial, papillary tumors before a small fraction of them advanced to invasion/metastasis. A genome-wide search of chromosomal imbalances by comparative genomic hybridization revealed that 9 of 11 (82%) of CIS had losses on chromosome 11. Southern blotting demonstrated the allelic loss of the p53 gene, which resides on mouse chromosome 11, in four comparative genomic hybridization-tested tumors and 10 of 11 (91%) additional CIS examined. Consistent with the reduced p53 gene dosage because of the allelic loss and the functional inactivation of p53 protein of the remaining allele by SV40T antigen, there was a dramatic decrease in CIS of Mdm-2, a major p53 target. In contrast, the level of p21, another p53 target, was largely unaltered, suggesting that p21 expression can be regulated by p53-independent mechanisms. These results delineate the early stages of bladder tumorigenesis and suggest that he loss of a p53-bearing chromosome is an early event in bladder tumorgenesis and is crucial for the genesis and the maintenance, but not the progression, of bladder CIS. On the basis of our current and previous transgenic studies, we have proposed an integrated pathway progression model of bladder cancer.

Original languageEnglish (US)
Pages (from-to)179-185
Number of pages7
JournalCancer Research
Volume63
Issue number1
StatePublished - Jan 1 2003

Fingerprint

Loss of Heterozygosity
p53 Genes
Carcinoma in Situ
Urinary Bladder
Maintenance
Chromosomes, Human, Pair 11
Comparative Genomic Hybridization
Transgenic Mice
Polyomavirus Transforming Antigens
Gene Dosage
Viral Tumor Antigens
Southern Blotting
Urinary Bladder Neoplasms
Neoplasms
Carcinogenesis
Chromosomes
Alleles
Genome
Neoplasm Metastasis
Antigens

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cheng, J., Huang, H., Pak, J., Shapiro, E., Sun, T. T., Cordon-Cardo, C., ... Wu, X. R. (2003). Allelic loss of p53 gene is associated with genesis and maintenance, but not invasion, of mouse carcinoma in situ of the bladder. Cancer Research, 63(1), 179-185.

Allelic loss of p53 gene is associated with genesis and maintenance, but not invasion, of mouse carcinoma in situ of the bladder. / Cheng, Jin; Huang, Hongying; Pak, Joanne; Shapiro, Ellen; Sun, Tung Tien; Cordon-Cardo, Carlos; Waldman, Frederic M.; Wu, Xue Ru.

In: Cancer Research, Vol. 63, No. 1, 01.01.2003, p. 179-185.

Research output: Contribution to journalArticle

Cheng, J, Huang, H, Pak, J, Shapiro, E, Sun, TT, Cordon-Cardo, C, Waldman, FM & Wu, XR 2003, 'Allelic loss of p53 gene is associated with genesis and maintenance, but not invasion, of mouse carcinoma in situ of the bladder', Cancer Research, vol. 63, no. 1, pp. 179-185.
Cheng, Jin ; Huang, Hongying ; Pak, Joanne ; Shapiro, Ellen ; Sun, Tung Tien ; Cordon-Cardo, Carlos ; Waldman, Frederic M. ; Wu, Xue Ru. / Allelic loss of p53 gene is associated with genesis and maintenance, but not invasion, of mouse carcinoma in situ of the bladder. In: Cancer Research. 2003 ; Vol. 63, No. 1. pp. 179-185.
@article{a06a96f7a93440b88674a4809a9635f5,
title = "Allelic loss of p53 gene is associated with genesis and maintenance, but not invasion, of mouse carcinoma in situ of the bladder",
abstract = "Carcinoma in situ (CIS) of the bladder has recently been proposed to be a heterogeneous group of diseases with varied histogenesis and biological behavior. In this study, we describe the sequential steps of CIS development and progression in a transgenic mouse model expressing low levels of the SV40 large T antigen. We found that CIS in transgenic mice arose from urothelial dysplasia, that CIS could persist for an extended period of time without invasion, and that the majority of CIS eventually evolved into high-grade, superficial, papillary tumors before a small fraction of them advanced to invasion/metastasis. A genome-wide search of chromosomal imbalances by comparative genomic hybridization revealed that 9 of 11 (82{\%}) of CIS had losses on chromosome 11. Southern blotting demonstrated the allelic loss of the p53 gene, which resides on mouse chromosome 11, in four comparative genomic hybridization-tested tumors and 10 of 11 (91{\%}) additional CIS examined. Consistent with the reduced p53 gene dosage because of the allelic loss and the functional inactivation of p53 protein of the remaining allele by SV40T antigen, there was a dramatic decrease in CIS of Mdm-2, a major p53 target. In contrast, the level of p21, another p53 target, was largely unaltered, suggesting that p21 expression can be regulated by p53-independent mechanisms. These results delineate the early stages of bladder tumorigenesis and suggest that he loss of a p53-bearing chromosome is an early event in bladder tumorgenesis and is crucial for the genesis and the maintenance, but not the progression, of bladder CIS. On the basis of our current and previous transgenic studies, we have proposed an integrated pathway progression model of bladder cancer.",
author = "Jin Cheng and Hongying Huang and Joanne Pak and Ellen Shapiro and Sun, {Tung Tien} and Carlos Cordon-Cardo and Waldman, {Frederic M.} and Wu, {Xue Ru}",
year = "2003",
month = "1",
day = "1",
language = "English (US)",
volume = "63",
pages = "179--185",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - Allelic loss of p53 gene is associated with genesis and maintenance, but not invasion, of mouse carcinoma in situ of the bladder

AU - Cheng, Jin

AU - Huang, Hongying

AU - Pak, Joanne

AU - Shapiro, Ellen

AU - Sun, Tung Tien

AU - Cordon-Cardo, Carlos

AU - Waldman, Frederic M.

AU - Wu, Xue Ru

PY - 2003/1/1

Y1 - 2003/1/1

N2 - Carcinoma in situ (CIS) of the bladder has recently been proposed to be a heterogeneous group of diseases with varied histogenesis and biological behavior. In this study, we describe the sequential steps of CIS development and progression in a transgenic mouse model expressing low levels of the SV40 large T antigen. We found that CIS in transgenic mice arose from urothelial dysplasia, that CIS could persist for an extended period of time without invasion, and that the majority of CIS eventually evolved into high-grade, superficial, papillary tumors before a small fraction of them advanced to invasion/metastasis. A genome-wide search of chromosomal imbalances by comparative genomic hybridization revealed that 9 of 11 (82%) of CIS had losses on chromosome 11. Southern blotting demonstrated the allelic loss of the p53 gene, which resides on mouse chromosome 11, in four comparative genomic hybridization-tested tumors and 10 of 11 (91%) additional CIS examined. Consistent with the reduced p53 gene dosage because of the allelic loss and the functional inactivation of p53 protein of the remaining allele by SV40T antigen, there was a dramatic decrease in CIS of Mdm-2, a major p53 target. In contrast, the level of p21, another p53 target, was largely unaltered, suggesting that p21 expression can be regulated by p53-independent mechanisms. These results delineate the early stages of bladder tumorigenesis and suggest that he loss of a p53-bearing chromosome is an early event in bladder tumorgenesis and is crucial for the genesis and the maintenance, but not the progression, of bladder CIS. On the basis of our current and previous transgenic studies, we have proposed an integrated pathway progression model of bladder cancer.

AB - Carcinoma in situ (CIS) of the bladder has recently been proposed to be a heterogeneous group of diseases with varied histogenesis and biological behavior. In this study, we describe the sequential steps of CIS development and progression in a transgenic mouse model expressing low levels of the SV40 large T antigen. We found that CIS in transgenic mice arose from urothelial dysplasia, that CIS could persist for an extended period of time without invasion, and that the majority of CIS eventually evolved into high-grade, superficial, papillary tumors before a small fraction of them advanced to invasion/metastasis. A genome-wide search of chromosomal imbalances by comparative genomic hybridization revealed that 9 of 11 (82%) of CIS had losses on chromosome 11. Southern blotting demonstrated the allelic loss of the p53 gene, which resides on mouse chromosome 11, in four comparative genomic hybridization-tested tumors and 10 of 11 (91%) additional CIS examined. Consistent with the reduced p53 gene dosage because of the allelic loss and the functional inactivation of p53 protein of the remaining allele by SV40T antigen, there was a dramatic decrease in CIS of Mdm-2, a major p53 target. In contrast, the level of p21, another p53 target, was largely unaltered, suggesting that p21 expression can be regulated by p53-independent mechanisms. These results delineate the early stages of bladder tumorigenesis and suggest that he loss of a p53-bearing chromosome is an early event in bladder tumorgenesis and is crucial for the genesis and the maintenance, but not the progression, of bladder CIS. On the basis of our current and previous transgenic studies, we have proposed an integrated pathway progression model of bladder cancer.

UR - http://www.scopus.com/inward/record.url?scp=0037228782&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037228782&partnerID=8YFLogxK

M3 - Article

VL - 63

SP - 179

EP - 185

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 1

ER -