Notch signaling as a therapeutic target for breast cancer treatment?

Abstract

Aberrant Notch signaling can induce mammary gland carcinoma in transgenic mice, and high expressions of Notch receptors and ligands have been linked to poor clinical outcomes in human patients with breast cancer. This suggests that inhibition of Notch signaling may be beneficial for breast cancer treatment. In this review, we critically evaluate the evidence that supports or challenges the hypothesis that inhibition of Notch signaling would be advantageous in breast cancer management. We find that there are many remaining uncertainties that must be addressed experimentally if we are to exploit inhibition of Notch signaling as a treatment approach in breast cancer. Nonetheless, Notch inhibition, in combination with other therapies, is a promising avenue for future management of breast cancer. Furthermore, since aberrant Notch4 activity can induce mammary gland carcinoma in the absence of RBPjκ, a better understanding of the components of RBPjκ-independent oncogenic Notch signaling pathways and their contribution to Notch-induced tumorigenesis would facilitate the deployment of Notch inhibition strategies for effective treatment of breast cancer.

Figure 1

Model for activation of multiple Notch signaling pathways. In the absence of Notch activity (that is, no NICD) (left), RBPjκ associates with transcription repressors to suppress the expression of canonical Notch target genes. Upon Notch activation under physiological conditions in which the NICD level is low (middle), NICD is assembled predominantly into the canonical NICD/RBPjκ/MAML complex that will activate the canonical Notch signaling pathway as well as affect the activity of other MAML- or even RBPjκ-interacting proteins by depriving them of MAML or RBPjκ. This is a result of the higher affinity of the NICD/RBPjκ/MAML complex compared with the non-canonical complexes. Upon aberrant Notch activation under oncogenic conditions (right) in which high levels of NICD saturate available MAML proteins, the affinity of NICD/RBPjκ dimer is not sufficient to prevent the formation of non-canonical NICD complexes. Consequently, a fraction of NICD will associate with other proteins such as NFκB and Smad3 as shown. With further increase in the NICD levels, other non-canonical NICD complexes will form in an ordered manner on the basis of their relative affinities and abundance. Each individual non-canonical NICD-containing protein complex will activate a signaling pathway (not necessarily to be a transcription-based pathway, which is shown) and the resulting cellular phenotype will reflect the combination of multiple signaling pathways. In this model, removing RBPjκ from cells will force the formation of non-canonical NICD complexes such as have been reported to be responsible for RBPjκ-independent Notch4 oncogenic activity. MAML, Mastermind-like protein; NFκB, nuclear factor-kappa-B; NICD, Notch intracellular domain.