Notch Signalling in Cancer: Oncogene or Tumour Suppressor

Signalling by Regulated Cleavage

A Notch receptor on one cell binds a ligand (Delta-like or Jagged) on a neighbouring cell. This pulling force exposes a cleavage site, and successive cuts by ADAM proteases and the gamma-secretase complex release the Notch intracellular domain.

That fragment travels to the nucleus, binds the transcription factor CSL, and converts it from a repressor to an activator of target genes such as HES and HEY family members and, in some contexts, MYC.

Notch as an Oncogene

In T-cell acute lymphoblastic leukaemia, more than half of cases carry activating NOTCH1 mutations that stabilise the intracellular domain or the receptor. Notch activation also promotes progression in some breast cancers and in adenoid cystic carcinoma.

In these settings Notch drives proliferation, survival and a stem-like state, and gamma-secretase inhibitors have been tested to shut it down, limited by gastrointestinal toxicity from blocking Notch in the gut.

Notch as a Tumour Suppressor

In squamous epithelia, notably skin, head and neck, lung and oesophagus, NOTCH1 and NOTCH2 carry recurrent loss-of-function mutations. Here Notch normally promotes differentiation and exit from the proliferative compartment, so losing it favours tumour growth.

This means the same drug strategy could help one cancer and harm another, which is why tissue context is central.

What Determines the Role

The direction of Notch's effect depends on the cell type, the differentiation state, the strength and duration of the signal, and crosstalk with other pathways. There is no simple rule that applies across cancers.

Genomic data help: activating mutations and amplifications point to an oncogenic role, while truncating and nonsense mutations point to tumour suppression.

Interpretation Notes

A NOTCH1 mutation on a report should be classified by type: an activating mutation in a leukaemia and a truncating mutation in a squamous cancer have opposite implications.

Notch pathway activity signatures are research tools, and no Notch-targeted drug is broadly approved in solid tumours.

Key Takeaways

• ·Notch signals by regulated cleavage that releases a transcription-activating fragment.
• ·It is oncogenic in T-cell leukaemia and some breast and salivary cancers.
• ·It is tumour-suppressive in squamous epithelia, where loss-of-function mutations recur.
• ·Mutation type (activating vs truncating) and tissue context determine the meaning.