Abstract
NUMB, and its close homologue NUMBL, behave as tumor suppressor genes by regulating the Notch pathway. The downregulation of these genes in tumors is common, allowing aberrant Notch pathway activation and tumor progression. However, some known differences between NUMB and NUMBL have raised unanswered questions regarding the redundancy and/or combined regulation of the Notch pathway by these genes during the tumorigenic process. We have found that NUMB and NUMBL exhibit mutual exclusivity in human tumors, suggesting that the associated tumor suppressor role is regulated by only one of the two proteins in a specific cell, avoiding duplicate signaling and simplifying the regulatory network. We have also found differences in gene expression due to NUMB or NUMBL downregulation. These differences in gene regulation extend to pathways, such as WNT or Hedgehog. In addition to these differences, the downregulation of either gene triggers a cancer stem cell-like related phenotype. These results show the importance of both genes as an intersection with different effects over cancer stem cell signaling pathways.