Inactivation of p53 and Pten promotes invasive bladder cancer
- Anna M. Puzio-Kuter1,2,3,
- Mireia Castillo-Martin1,2,4,
- Carolyn W. Kinkade1,2,3,
- Xi Wang2,5,6,
- Tian Huai Shen2,4,
- Tulio Matos2,4,
- Michael M. Shen2,5,6,
- Carlos Cordon-Cardo1,2,4,8 and
- Cory Abate-Shen1,2,3,4,7
- 1Department of Urology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA;
- 2Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA;
- 3Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA;
- 4Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA;
- 5Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA;
- 6Department of Genetics and Development, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA
Abstract
Although bladder cancer represents a serious health problem worldwide, relevant mouse models for investigating disease progression or therapeutic targets have been lacking. We show that combined deletion of p53 and Pten in bladder epithelium leads to invasive cancer in a novel mouse model. Inactivation of p53 and PTEN promotes tumorigenesis in human bladder cells and is correlated with poor survival in human tumors. Furthermore, the synergistic effects of p53 and Pten deletion are mediated by deregulation of mammalian target of rapamycin (mTOR) signaling, consistent with the ability of rapamycin to block bladder tumorigenesis in preclinical studies. Our integrated analyses of mouse and human bladder cancer provide a rationale for investigating mTOR inhibition for treatment of patients with invasive disease.
Keywords
Footnotes
-
↵7 Corresponding authors.
↵E-MAIL cabateshen{at}columbia.edu; FAX (212) 851-4572.
-
↵8 E-MAIL cordon-c{at}columbia.edu; FAX (212) 851-4550.
-
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1772909.
-
Supplemental material is available at http://www.genesdev.org.
-
- Received December 15, 2008.
- Accepted January 30, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press
