Notch Signaling Activation as a Hallmark for Triple-Negative Breast Cancer Subtype

Figure 2

Notch-targeting therapeutic approaches in TNBCs. (a) The canonical Notch signaling pathway: ligand binding promotes sequential cleavages of the Notch receptors (Notch1-4) by ADAM enzyme and γ-secretase complex, resulting in the release of NICD, which translocates in the nucleus, interacts with transcriptional regulators to transcriptionally activate the canonical Notch target genes (ON), thus leading to the regulation of TNBC growth and progression. (b) Notch inhibitors with lower or absent selectivity, respectively, include mAbs targeting the Notch ligands and GSIs. (1) mAbs against Notch ligands prevent ligand-receptor interaction and the subsequent Notch cleavages, preventing Notch signaling triggering. Little is known about the specific Notch-ligand relationship in TNBC; thus further studies are needed to consider ligand blocking as a potential alternative selective approach in TNBC treatment. (2) GSIs act as pan-Notch inhibitors since they prevent the cleavage of all Notch receptors, thus avoiding the release of any NICD. This unselective mechanism of action is strongly correlated with a high intestinal toxicity in patients, which significantly impairs their clinical use. (3) Lower doses of GSIs used in combination with chemotherapeutic drugs result in improved clinical outcome and less toxicity, which however must be overcome. (c) A higher selectivity can be obtained by using monoclonal antibodies directed against the extracellular domain of a specific Notch receptor (1): mAbs mask the cleavage domain of ADAM, thus preventing the binding of this enzyme and the subsequent γ-secretase cleavage. The final effect will depend on the specific block of the single Notch receptor, also used in combination with chemotherapeutic drugs (2). Several studies detailed in the text have suggested that a greater selectivity in the Notch inhibition approach for TNBCs treatment is strongly correlated with a higher probability of success in favoring tumor regression, associated with less toxicity and therefore with a potential better prognosis of TNBC-bearing patients. Abbreviations. ADAM: a disintegrin and metalloproteinase; CSL: CBF1/Su(H)/Lag-1; CoA: coactivator; CoR: corepressor; GSIs: γ-secretase inhibitors; mAb: monoclonal antibody; MAML1: mastermind-like 1; NECD: Notch extracellular domain; NICD: Notch intracellular domain; NTM: Notch transmembrane; PM: plasmatic membrane.

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