This is the second renewal of our Program Project that has been in existence for over 10 years and which has been highly productive and interactive. The goals of this program will be realized through an interdisciplinary and collaborative approach to understand the roles of mutant p53, p53 family member's p63 and p73 and new tumor suppressor genes in cancer. Our approaches include cell biology, proteomics, microscopy, bioinformatics, functional genomics, mouse modeling and human and mouse pathology. As this program has progressed, our research has become more translational and relevant to human disease, now focusing on breast, bladder and lymphoma tumor genesis. Carol Prives will employ the 3D culture protocol to examine the roles of mutant p53 and p53 homologues (P63 and p73) in mammary cell morphology and oncogenic transformation. She will also characterize the mechanisms of ANp63 protein turnover in these contexts. Arnold Levine will pursue the observation that breast cancer cells with mutant p53 have a stem cell gene expression signature, and will test mutant p53 allele-specific drugs that were identified by novel bioinformatic approaches for treatment of cancer cells. Levine will also study the roles of SNPs in p63 or p73 that influence DNA repair systems in female eggs and copy number variation that affect cancer in offspring Scott Lowe will continue to study the genetic and molecular basis of lymphoma. He will perform shRNA screens using the Ep-Myc B cell model to identify new tumor suppressor genes. He will also examine the role of genes co-deleted with p53 in lymphoma on chromosome 17p testing the hypothesis that such genes may also have tumor suppressive activity. Additionally Lowe will study the impact of reactivation of latent p53 by down-regulation of Mdm2, as well as perform an shRNA screen to identify genes whose inhibition facilitates death of mutant-p53 dependent tumors. Cordon-Cardo will focus on p63 expression and roles in normal and cancerous bladder tissue in mice and humans. He will use specific shRNAs to characterize the impact of p63 isoforms during urothelial development in mice, and determine the expression of p63 isoforms in bladder carcinoma. Cordon-Cardo will also pursue identification of bladder stem cells and the mechanisms by which they are chemoresistant. This program is highly dependent on the functioning of cores that support the administration, histopathology, shRNAs, mouse modeling and bioinfomatics that is required for the proposed experiments. The projects are even more interdependent and interactive than before and as a result much of the proposed research cannot be done effectively without the support of this program.

Public Health Relevance

It is the goal of this program to understand and exploit the p53 network for improving cancer diagnoses id treatment. The proposed research will provide new insights into how loss or mutation of p53 results information of a tumor. It will also reveal how and when p53 family members, p63 and p73, play roles in cancer progression. New approaches to treating tumor cells will be tested. Finally, the role and presence of stem cells tumors will be evaluated.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA087497-12
Application #
8323270
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (M1))
Program Officer
Watson, Joanna M
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
$1,777,337
Indirect Cost
$335,933
Name
Columbia University (N.Y.)
Department
Biology
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Miething, Cornelius; Scuoppo, Claudio; Bosbach, Benedikt et al. (2014) PTEN action in leukaemia dictated by the tissue microenvironment. Nature 510:402-6
Jia, A Y; Castillo-Martin, M; Bonal, D M et al. (2014) MicroRNA-126 inhibits invasion in bladder cancer via regulation of ADAM9. Br J Cancer 110:2945-54
Barber, Alison G; Castillo-Martin, Mireia; Bonal, Dennis M et al. (2014) Characterization of desmoglein expression in the normal prostatic gland. Desmoglein 2 is an independent prognostic factor for aggressive prostate cancer. PLoS One 9:e98786
Chen, Chong; Liu, Yu; Rappaport, Amy R et al. (2014) MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell 25:652-65
Jia, Angela Y; Castillo-Martin, Mireia; Domingo-Domenech, Josep et al. (2013) A common MicroRNA signature consisting of miR-133a, miR-139-3p, and miR-142-3p clusters bladder carcinoma in situ with normal umbrella cells. Am J Pathol 182:1171-9
Mills, John R; Malina, Abba; Lee, Teresa et al. (2013) RNAi screening uncovers Dhx9 as a modifier of ABT-737 resistance in an E?-myc/Bcl-2 mouse model. Blood 121:3402-12
Freed-Pastor, William A; Mizuno, Hideaki; Zhao, Xi et al. (2012) Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148:244-58
Shen, Tian Huai; Gladoun, Nataliya; Castillo-Martin, Mireia et al. (2012) A BAC-based transgenic mouse specifically expresses an inducible Cre in the urothelium. PLoS One 7:e35243
Karni-Schmidt, Orit; Castillo-Martin, Mireia; Shen, Tian Huai et al. (2011) Distinct expression profiles of p63 variants during urothelial development and bladder cancer progression. Am J Pathol 178:1350-60
Wosnitzer, Matthew S; Domingo-Domenech, Josep; Castillo-Martin, Mireia et al. (2011) Predictive value of microtubule associated proteins tau and stathmin in patients with nonmuscle invasive bladder cancer receiving adjuvant intravesical taxane therapy. J Urol 186:2094-100

Showing the most recent 10 out of 68 publications