Abstract
The Notch signalling pathway is a highly conserved developmental signalling pathway, with vital roles in determining cell fate during embryonic development and tissue homeostasis. Aberrant Notch signalling has been implicated in many disease pathologies, including cancer. In this review, we will outline the mechanism and regulation of the Notch signalling pathway. We will also outline the role Notch signalling plays in normal mammary gland development and how Notch signalling is implicated in breast cancer tumorigenesis and progression. We will cover how Notch signalling controls several different hallmarks of cancer within epithelial cells with sections focussed on its roles in proliferation, apoptosis, invasion, and metastasis. We will provide evidence for Notch signalling in the breast cancer stem cell phenotype, which also has implications for therapy resistance and disease relapse in breast cancer patients. Finally, we will summarise the developments in therapeutic targeting of Notch signalling, and the pros and cons of this approach for the treatment of breast cancer.
Highlights
At the turn of millennium, there was growing interest in the role Notch signalling played in tissue homeostasis and the aetiology of human diseases
Within the normal mammary gland, Notch signalling is important in driving multipotent foetal mammary stem cells (MaSCs) into the unipotent luminal progenitor cell fate and in maintaining the progenitor fate through puberty and adult life
In breast cancer, elevated Notch signalling is seen in all cancers but it is associated with triple negative breast cancer (TNBC) and cancers that show therapy resistance where elevated Notch signalling is associated with poor prognosis
Summary
At the turn of millennium, there was growing interest in the role Notch signalling played in tissue homeostasis and the aetiology of human diseases. The functional studies have shown that Notch signalling drives MaSCs toward the luminal progenitor cell fate and maintains cells in this fate preventing their terminal differentiation (Dontu et al, 2004; Buono et al, 2006; Bouras et al, 2008; Raouf et al, 2008; Zhang Y. et al, 2016) Maintaining this proliferative cell fate could explain why tumour development is seen in transgenic and knockout mouse models where Notch signalling is activated in the mammary gland (Smith et al, 1995; Kiaris et al, 2004; Hu et al, 2006). Pharmacological inhibition of Notch signalling was sufficient to reduce breast cancer bone metastasis and osteolysis in vivo, implying that targeting Notch signalling may be a suitable therapeutic approach for inhibiting breast cancer metastasis (Sethi et al, 2011)
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