Abstract
Breast cancer is the second most common malignancy, worldwide. Treatment decisions are based on tumor stage, histological subtype, and receptor expression and include combinations of surgery, radiotherapy, and systemic treatment. These, together with earlier diagnosis, have resulted in increased survival. However, initial treatment efficacy cannot be guaranteed upfront, and these treatments may come with (long-term) serious adverse effects, negatively affecting a patient's quality of life. Gene expression-based tests can accurately estimate the risk of recurrence in early stage breast cancers. Disease recurrence correlates with treatment resistance, creating a major need to resensitize tumors to treatment. Notch signaling is frequently deregulated in cancer and is involved in treatment resistance. Preclinical research has already identified many combinatory therapeutic options where Notch involvement enhances the effectiveness of radiotherapy, chemotherapy or targeted therapies for breast cancer. However, the benefit of targeting Notch has remained clinically inconclusive. In this review, we summarize the current knowledge on targeting the Notch pathway to enhance current treatments for breast cancer and to combat treatment resistance. Furthermore, we propose mechanisms to further exploit Notch-based therapeutics in the treatment of breast cancer.
Highlights
The E3 ligase MDM2 has been shown to contribute to the degradation of Numb and through ubiquitination leading to activation of Notch in breast cancer
High Notch1 and HIF predict a worse prognosis [133]. These results show that Notch1 signaling is important for epithelial-mesenchymal transition (EMT) and downregulation of E-cadherin, creating a more invasive phenotype
Docetaxel treatment increased EMT markers SNAIL, SLUG and N-cadherin, which could be blocked by Notch inhibition. These findings indicate that Notch1 is involved in the resistance mechanisms of docetaxel treated tumors and that dual treatment could block enrichment of the breast cancer stem cells (BCSCs) population and increase therapy efficacy
Summary
J. Mollen , 1,2,3† Jonathan Ient 1†, Vivianne C. Boersma 1,2, Lucio Miele 5,6, Marjolein L. Harvard Medical School, United States Isabella Screpanti, Università degli Studi di Roma La. Specialty section: This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal
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