Targeting Notch degradation system provides promise for breast cancer therapeutics

•Notch is a family of highly conserved protein with simplistic molecular design but diverse functions.•Degradation of Notch 1-4 in breast cancer is respectively assessed.•Notch 1-4 harbor controversial values in breast cancer, thus their use as theranostics requires further validation.•Notch profiling could assist the identification of patients with breast cancer who are likely to benefit from Notch-inhibition strategies.•The use of inhibitors of Notch signaling pathways is a promising therapeutic alternative in patients with breast cancer.

Notch receptor signaling pathways play an important role, not only in normal breast development but also in breast cancer development and progression. As a group of ligand-induced proteins, different subtypes of mammalian Notch (Notch1-4) are sensitive to subtle changes in protein levels. Thus, a clear understanding of mechanisms of Notch protein turnover is essential for understanding normal and pathological mechanisms of Notch functions. It has been suggested that there is a close relationship between the carcinogenesis and the dysregulation of Notch degradation. However, this relationship remains mostly undefined in the context of breast cancer, as protein degradation is mediated by numerous signaling pathways as well as certain molecule modulators (activators/inhibitors). In this review, we summarize the published data regarding the regulation of Notch family member degradation in breast cancer, while emphasizing areas that are likely to provide new therapeutic modalities for mechanism-based anti-cancer drugs.