Moving Breast Cancer Therapy up a Notch

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.

Keywords: Notch; breast cancer; personalized precision treatment; resensitisation; treatment resistance.

Figure 1

Notch receptor maturation, ligand dependent and independent activation pathway and targetable steps. Representation of Notch receptor maturation, ligand dependent and independent activation and the key enzymes involved. Text in red represents steps that can be targeted. The red star in Notch extracellular domain represents Notch activating mutations leading to ligand independent signaling. (CBF1, Su(H), Lag1), CSL; NICD, Notch intracellular domain and MAML, Mastermind-Like.

Figure 2

Notch receptor maturation and pathway activation, targetable options, and receptor functionality. (A) Stepwise representation of the process of Notch receptor maturation until receptor activation, followed by transcriptional output (not shown), and possibilities in targeting the Notch receptor pathway. (B) Notch receptor functional domains and corresponding functions ANK, Ankyrin repeats; LNR, Lin12-Notch Repeats and RAM, RBP-jk association module.

Figure 3

Overview of the role and opportunities for Notch in breast cancer therapy. Summary of the 4 fields of breast cancer therapy [radiotherapy, chemotherapy, endocrine therapy, and targeted therapy (HER2)] in which Notch targeting can play a significant role.