The NOTCH Pathway Plays a Tumor Suppressive Role in Bladder Cancer

NOTCH signaling regulates a number of cellular processes, including proliferation, differentiation, and apoptosis, and has been implicated as either an oncogene or a tumor suppressor in various tumor types. Using full-exon sequencing, Rampias and colleagues identified somatic loss-of-function mutations in NOTCH pathway components, in particular the NOTCH1 and NOTCH2 receptors, in 43% of human bladder transitional cell carcinoma (TCC) samples examined. In addition, the NOTCH1 locus was subject to frequent copy-number loss, which was associated with NOTCH1 mutation in several cases, suggestive of LOH. Inactivation of the NOTCH pathway was associated with decreased expression of NOTCH target genes and correlated with shorter overall survival in patients with superficial or muscle-invasive bladder cancer. Sequencing of known bladder cancer oncogenes, including FGFR3, RAS, and PIK3CA, showed only partial overlap with NOTCH pathway mutations and NOTCH1 copy-number loss. Furthermore, tumors with NOTCH inactivation, either alone or in combination with FGFR3 or RAS mutations, exhibited increased phosphorylation of ERK1/2, suggesting that NOTCH negatively regulates ERK1/2 activation. Consistent with this idea, activation of NOTCH signaling inhibited the proliferation of TCC cell lines and diminished the phosphorylation of ERK1/2, but not upstream signaling components, by directly inducing the transcription of several dual-specificity phosphatases (DUSP), which mediate dephosphorylation of ERK1/2. Genetic inactivation of NOTCH signaling in mice promoted the development of high-grade invasive urothelial carcinomas characterized by ERK1/2 phosphorylation and expression of basal cell markers, similar to the aggressive basal subtype of bladder cancer in humans, whereas overexpression of activated NOTCH1 reversed the cancer phenotype. Similarly, urothelium-specific loss of NOTCH signaling also resulted in the formation of bladder tumors with basal characteristics. In sum, these data implicate loss of NOTCH signaling as a driver event in bladder cancer and suggest that reactivation of the NOTCH pathway may be therapeutically beneficial.

Rampias T, Vgenopoulou P, Avgeris M, Polyzos A, Stravodimos K, Valavanis C, et al. A new tumor suppressor role for the NOTCH pathway in bladder cancer. Nat Med 201420:1199–205.

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