Notch signaling in breast cancer: From pathway analysis to therapy. (1st October 2019)

• Record Type: Journal Article
• Authors: Krishna, B. Madhu; Jana, Samir; Singhal, Jyotsana; Horne, David; Awasthi, Sanjay; Salgia, Ravi; Singhal, Sharad S.
• Is Part Of: Cancer letters. Volume 461(2019)
• Page Start: 123
• Page End: 131
• Publication Date: 2019-10-01
• Subjects: Breast cancer -- Notch receptor -- γ-secretase inhibitors -- Monoclonal antibodies -- Chemo-resistance; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.07.012
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The Notch signaling pathway, which is highly conserved from sea urchins to humans, plays an important role in cell-differentiation, survival, proliferation, stem-cell renewal, and determining cell fate during development and morphogenesis. It is well established that signaling pathways are dysregulated in a wide-range of diseases, including human malignancies. Studies suggest that the dysregulation of the Notch pathway contributes to carcinogenesis, cancer stem cell renewal, angiogenesis, and chemo-resistance. Elevated levels of Notch receptors and ligands have been associated with cancer-progression and poor survival. Furthermore, the Notch signaling pathway regulates the transcriptional activity of key target genes through crosstalk with several other signaling pathways. Indeed, increasing evidence suggests that the Notch signaling pathway may serve as a therapeutic target for the treatment of several cancers, including breast cancer. Researchers have demonstrated the anti-tumor properties of Notch inhibitors in various cancer types. Currently, Notch inhibitors are being evaluated for anticancer efficacy in a number of clinical-trials. However, because there are multiple Notch receptors that can exhibit either oncogenic or tumor-suppressing roles in various cells, it is important that the Notch inhibitors are specific to particular receptors that are tumorigenic in nature. This review critically evaluates existing Notch inhibitory drugs and strategies and summarizes the previous discoveries, current understandings, and recent developments in support of Notch receptors as therapeutic targets in breast cancer. Highlights: Notch receptors can behaves as either oncogene or tumor suppressor depending on cellular context. Elevated levels of Notch1, Notch4 and Dll4 are observed in several cancers and are correlated with poor prognosis. Inhibition of Notch signaling pathway using γ-secretase inhibitors (GSIs) can deliver promising tumor suppressor results. Natural products are also found to be playing an important role in the inhibition of Notch signaling pathway. This review suggests that Notch signaling pathway can be therapeutic target for the treatment of breast cancer.