Notch-out for breast cancer therapies

Notch signalling is an evolutionarily highly conserved pathway that plays a crucial role during embryonic development and in tissue homeostasis maintenance during adult life. Abnormal Notch signalling has been implicated in several human genetic disorders and in multiple facets of cancer biology, including stem cell renewal, cancer cell proliferation, tumor angiogenesis and metastasis. Hence, Notch signalling has gained increasing attention as a potential therapeutic target for many disorders. gamma-secretase inhibitors (GSIs) were the first therapeutics used to inhibit pathological Notch signalling in various diseases, notably in oncology. Although GSIs show antitumor activity in advanced and metastatic cancer, the lack of substrate specificity and associated toxicity constitute significant limitations to their therapeutic use. Antibodies have emerged as powerful therapeutics due to their specificity, efficacy and safety, and remarkable success has been achieved with their use in immune-mediated diseases and cancer. This review describes the importance of the Notch pathway and its involvement in several pathologies, with a special focus on breast cancer. Moreover, the role of Notch and its ligands as promising therapeutic targets will be addressed, as well as therapeutic strategies being pursued for Notch modulation.