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.