A Role for Notch Signalling in Breast Cancer and Endocrine Resistance

Abstract

Over the past decade, there has been growing interest in the Notch signalling pathway within the breast cancer field. This interest stemmed initially from the observation that Notch signalling is aberrantly activated in breast cancer and its effects on various cellular processes including proliferation, apoptosis, and cancer stem cell activity. However more recently, elevated Notch signalling has been correlated with therapy resistance in oestrogen receptor-positive breast cancer. As a result, inhibiting Notch signalling with therapeutic agents is being explored as a promising treatment option for breast cancer patients.

Figure 1

Basics of Notch signalling pathway. Notch signalling activation occurs via an interaction between DSL ligand and Notch receptor on adjacent cells. This interaction leads to force being applied to the extracellular domain of Notch, as DSL ligand undergoes endocytosis into the signalling cell, leading to a conformational change within the negative regulatory region (NRR). This conformational change exposes a cleavage site (S2) for the ADAM10 and ADAM17 proteases. The extracellularly truncated Notch protein then undergoes cleavage at site 3 (S3), mediated by γ-secretase, which releases the Notch intracellular domain (NICD). Finally, NICD translocates into the nucleus and interacts with the DNA binding protein RBPj and the transcriptional coactivators MAML and p300 to initiate transcription of downstream targets including the Hes and Hey family of genes.