The many facets of Notch signaling in breast cancer: toward overcoming therapeutic resistance

Abstract

Breast cancer is the second leading cause of cancer-related death in women and is a complex disease with high intratumoral and intertumoral heterogeneity. Such heterogeneity is a major driving force behind failure of current therapies and development of resistance. Due to the limitations of conventional therapies and inevitable emergence of acquired drug resistance (chemo and endocrine) as well as radio resistance, it is essential to design novel therapeutic strategies to improve the prognosis for breast cancer patients. Deregulated Notch signaling within the breast tumor and its tumor microenvironment (TME) is linked to poor clinical outcomes in treatment of resistant breast cancer. Notch receptors and ligands are also important for normal mammary development, suggesting the potential for conserved signaling pathways between normal mammary gland development and breast cancer. In this review, we focus on mechanisms by which Notch receptors and ligands contribute to normal mammary gland development and breast tumor progression. We also discuss how complex interactions between cancer cells and the TME may reduce treatment efficacy and ultimately lead to acquired drug or radio resistance. Potential combinatorial approaches aimed at disrupting Notchand TME-mediated resistance that may aid in achieving in an improved patient prognosis are also highlighted.Breast cancer is the most prevalent cancer among women worldwide (ShahidSales et al. 2018;Ghasemi et al. 2019). Breast cancer is a highly heterogeneous disease with many subtypes, and treatment choice is based on the presence or absence of different hormone receptors, such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as well as tumor grade and age of the patient (Desmedt et al. 2008). Unfortunately, traditional treatment methods, including chemotherapy, endocrine therapy, and radiation therapy are often not curative, and only im-prove clinical outcome (Schmidberger et al. 2003;

Clinical Significance of Notch Receptors In Triple Negative Breast Cancer

“…There are four known Notch paralogs which display different patterns in their expression and function across different malignancies. Oncogenic role of Notch signaling was rst reported in T-ALL [17] and later reported in lung cancer, ovarian cancer, breast cancer, colorectal cancer [18,19,20,21,22] while tumor suppressive role of Notch signaling was reported in pancreatic cancer and hepatocellular carcinoma [23,24]. However, research about relationship between Notch receptors and TNBC, and the association among the Notch receptors is limited and unclear.…”

Notch Signaling in Breast Tumor Microenvironment as Mediator of Drug Resistance

“…Chromosome 9–7 translocation that generates a constitutively active form of Notch1 causes the Notch signaling dysregulation which is involved in T-Cell Acute Lymphoblastic Leukemia (T-ALL) [ 30 ]. Actually, genome-scale sequencing studies identified mutations in Notch genes leading to inappropriate or dysregulated activation of Notch signaling in colorectal cancer [ 31 ], glioblastoma [ 32 ], BC [ 12 , 33 ] and other malignancies [ 28 ]. Notch pathway stimulation causes inhibition of apoptosis, induction of proliferation and epithelial mesenchymal transition (EMT), maintenance of a stem-like phenotype, induction of angiogenesis, promotion of metastasis and drug resistance, and other tumor–stroma interactions that are less specific to individual tumor types [ 28 ].…”

“…Numerous studies confirm that the Notch pathway has a major participation in BC progression and therapy resistance [ 12 ]. Notch activation is a hallmark of the TNBC [ 13 ] and contributes to the pathogenesis of human BC by affecting multiple cellular processes, including cancer stem cell maintenance, cell fate specification and differentiation [ 14 ].…”

To Be, or Notch to Be: Mediating Cell Fate from Embryogenesis to Lymphopoiesis

“…Whilst we have focused on aberrant Notch signaling in hematological malignancies, supraphysiological Notch signaling also contributes to solid cancers. Notch gainof-function mutations are associated with breast cancer [110,111], glioblastoma [112,113], and adenoid cystic carcinoma [114]. Notch loss-of-function mutations are well charac-terized in squamous cell carcinoma [114], small cell lung cancer [114,115], and colorectal cancer [114,116].…”