Journal
NATURE MEDICINE
Volume 20, Issue 10, Pages 1199-1205Publisher
NATURE PORTFOLIO
DOI: 10.1038/nm.3678
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Funding
- Marie Curie Reintegration grant [224821]
- Greek General Secretariat for Research and Technology 'Excellence' grant [UTN_1466]
- Fondation Sante Grant in Biomedical Sciences
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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(1). This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor(2). 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(3). Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified(4,5). 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.
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