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Published on: January 12, 2020
Notch Signaling in Breast Cancer: A Role in Drug Resistance
McKenna BeLow1, Clodia Osipo1,2,3
1Integrated Cell Biology Program, Loyola University Chicago, Maywood, IL 60513, USA.
Abstract:
Breast cancer is a heterogeneous disease that can be subdivided into unique molecular subtypes based on protein expression of the Estrogen Receptor, Progesterone Receptor, and/or the Human Epidermal Growth Factor Receptor 2. Therapeutic approaches are designed to inhibit these overexpressed receptors either by endocrine therapy, targeted therapies, or combinations with cytotoxic chemotherapy. However, a significant percentage of breast cancers are inherently resistant or acquire resistance to therapies, and mechanisms that promote resistance remain poorly understood. Notch signaling is an evolutionarily conserved signaling pathway that regulates cell fate, including survival and self-renewal of stem cells, proliferation, or differentiation. Deregulation of Notch signaling promotes resistance to targeted or cytotoxic therapies by enriching of a small population of resistant cells, referred to as breast cancer stem cells, within the bulk tumor; enhancing stem-like features during the process of de-differentiation of tumor cells; or promoting epithelial to mesenchymal transition. Preclinical studies have shown that targeting the Notch pathway can prevent or reverse resistance through reduction or elimination of breast cancer stem cells. However, Notch inhibitors have yet to be clinically approved for the treatment of breast cancer, mainly due to dose-limiting gastrointestinal toxicity. In this review, we discuss potential mechanisms of Notch-mediated resistance in breast cancer cells and breast cancer stem cells, and various methods of targeting Notch through γ-secretase inhibitors, Notch signaling biologics, or transcriptional inhibitors. We also discuss future plans for identification of novel Notch-targeted therapies, in order to reduce toxicity and improve outcomes for women with resistant breast cancer.
Insights
Notch signaling deregulation drives resistance in breast cancer by promoting cancer stem cells. Targeting Notch may reverse resistance, but clinical application is limited by toxicity, necessitating novel therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Breast cancer is a heterogeneous disease with subtypes classified by Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2) expression.
- Therapies targeting these receptors are common, but intrinsic or acquired resistance limits treatment efficacy.
- Mechanisms underlying therapeutic resistance in breast cancer are not fully understood.
Purpose of the Study:
- To review the mechanisms of Notch signaling in promoting breast cancer resistance.
- To discuss strategies for targeting Notch signaling to overcome therapeutic resistance.
- To explore future directions for developing novel Notch-targeted therapies with reduced toxicity.
Main Methods:
- Review of preclinical and clinical studies on Notch signaling in breast cancer.
- Analysis of mechanisms of Notch-mediated resistance, including breast cancer stem cells (BCSCs) and epithelial-to-mesenchymal transition (EMT).
- Evaluation of different therapeutic approaches targeting Notch signaling, such as gamma-secretase inhibitors and biologics.
Main Results:
- Deregulation of Notch signaling contributes to therapeutic resistance by enriching BCSCs and promoting stem-like features or EMT.
- Preclinical data suggest that inhibiting Notch signaling can reduce BCSCs and reverse resistance.
- Current Notch inhibitors face challenges with dose-limiting toxicities, hindering clinical approval.
Conclusions:
- Notch signaling plays a critical role in the development and maintenance of therapy-resistant breast cancer.
- Targeting Notch signaling holds promise for overcoming resistance, but toxicity remains a significant hurdle.
- Further research is needed to identify safer and more effective Notch-targeted therapies for resistant breast cancer.
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