Format

Send to

Choose Destination
Nat Med. 2014 Oct;20(10):1199-205. doi: 10.1038/nm.3678. Epub 2014 Sep 7.

A new tumor suppressor role for the Notch pathway in bladder cancer.

Author information

1
Biomedical Research Foundation Academy of Athens, Athens, Greece.
2
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, Athens, Greece.
3
First Department of Urology, 'Laiko' General Hospital, Medical School, University of Athens, Athens, Greece.
4
Molecular Pathology Unit, Department of Pathology, Metaxa Cancer Hospital, Piraeus, Greece.

Abstract

The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner. This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor. Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States. Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.

PMID:
25194568
DOI:
10.1038/nm.3678
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center