Project 4: Roles and Regulation of Mutant p53 and p63 Isoforms in Urothelial Development and Bladder Cancer Progression Carlos Cordon-Cardo, M.D., Ph.D. Cumulative observations by our group led us to hypothesize that the molecular processes by which p53 and p63 regulate urothelial differentiation are causally linked to their role in bladder tumor initiation and progression. Our main objective is to define the critical functions of p53 and p63-isoforms in urothelial development, bladder cancer initiation and progression. For this purpose, we will use state-ofthe- art molecular pathology and genetic approaches utilizing in vitro cell-based assays and in vivo mouse models, validating significant findings in human normal and tumor bladder tissues.
The specific aims are:
Aim #1. Comprehensive analysis of p53 and p63-isoforms during urothelial development. We discovered that p63 is essential for urothelial differentiation, and that p63-null mice developed an abnormal mono-cellular layer urothelium. Prelimianry data supports that this layer is constituted of

Public Health Relevance

Understanding critical processes regulated by p53 family members implicated in urothelial development and bladder tumor initiation will enhance our search for urothelial stem cells and related bladder cancer stem cells. Our studies have significant translational implications through the definition of a novel urothelial histogenesis model based on p63-differentiation pathways, determining and validating the predictive nature of p53 and p63 alterations in bladder cancer, and identifying candidate bladder cancer stem cells. In sum, results from these studies will have far reaching implications regarding bladder cancer prognosis and establishing effective treatment, thus assisting in the implementation of

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA087497-12
Application #
8555165
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (M1))
Project Start
2000-09-30
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
12
Fiscal Year
2012
Total Cost
$450,278
Indirect Cost
$85,106
Name
Columbia University (N.Y.)
Department
Type
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Castillo-Martin, Mireia; Collazo Lorduy, Ana; Gladoun, Nataliya et al. (2016) H-RAS mutation is a key molecular feature of pediatric urothelial bladder cancer. A detailed report of three cases. J Pediatr Urol 12:91.e1-7
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Barber, Alison G; Castillo-Martin, Mireia; Bonal, Dennis M et al. (2015) PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer. Cancer Med 4:1258-71
Chakraborty, A A; Scuoppo, C; Dey, S et al. (2015) A common functional consequence of tumor-derived mutations within c-MYC. Oncogene 34:2406-9

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