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.
Highlights
Breast Cancer and Drug ResistanceBreast cancer remains the second leading cause of cancer-related death in women worldwide
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
Current studies are investigating the plasticity of Breast Cancer Stem Cells (BCSCs) to transition between epithelial-to-mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET) states and how this may contribute to therapy resistance and metastatic-tumor development [61,62,82,83]
Summary
Breast cancer remains the second leading cause of cancer-related death in women worldwide. These tumors are effectively targeted by using first-line humanized, monoclonal antibodies, including trastuzumab and pertuzumab [8,9,10], or, later, second-line tyrosine kinase inhibitors, such as lapatinib [11] or neratinib [12,13,14]. Breast cancers that lack expression of the ER, PR, and overexpression of HER2 are classified as triple negative and treated with cytotoxic chemotherapy due to lack of approved targeted therapy [15,16,17,18]. Triple negative breast cancers are inherently resistant to HER2 or ER-targeted therapies and are treated with cytotoxic chemotherapy, such as taxane-based, platin-based, and other DNA-damaging agents [22]. It is critical to elucidate potential mechanisms of drug resistance in breast cancer, in order to improve survival outcomes for women
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