Abstract
Members of the Notch family and chronic inflammation were each separately demonstrated to have prominent malignancy-supporting roles in breast cancer. Recent investigations indicate that bi-directional interactions that exist between these two pathways promote the malignancy phenotype of breast tumor cells and of their tumor microenvironment. In this review article, we demonstrate the importance of Notch-inflammation interplays in malignancy by describing three key networks that act in breast cancer and their impacts on functions that contribute to disease progression: (1) Cross-talks of the Notch pathway with myeloid cells that are important players in cancer-related inflammation, focusing mainly on macrophages; (2) Cross-talks of the Notch pathway with pro-inflammatory factors, exemplified mainly by Notch interactions with interleukin 6 and its downstream pathways (STAT3); (3) Cross-talks of the Notch pathway with typical inflammatory transcription factors, primarily NF-κB. These three networks enhance tumor-promoting functions in different breast tumor subtypes and act in reciprocal manners, whereby Notch family members activate inflammatory elements and vice versa. These characteristics illustrate the fundamental roles played by Notch-inflammation interactions in elevating breast cancer progression and propose that joint targeting of both pathways together may provide more effective and less toxic treatment approaches in this disease.
Highlights
The Notch pathway controls many developmental processes, where it dictates cell fate determination, differentiation and tissue homeostasis
The findings summarized above on networks established between the Notch pathway and interleukin 6 (IL-6) portrayed the tight interplay that exists between Notch receptors/ligands with STAT3 in Breast cancer (BC); several lines of evidence addressed the interactions of Notch family members with JNK/AP-1 in BC [112,113]
In analyses of the molecular mechanisms we found that following tumor necrosis factor α (TNFα) stimulation of such co-cultures, p65 was activated in both cell types but more so in the cancer cells; p65 activation mainly in TNBC cells, and in the mesenchymal stromal cells (MSCs), up-regulated the expression and activation of Notch1 in the tumor cells, which promoted CXCL8 production primarily in the cancer cells [98] (Figure 1(C2))
Summary
The Notch pathway controls many developmental processes, where it dictates cell fate determination, differentiation and tissue homeostasis (representative review articles: [1,2,3,4,5,6]). To illustrate the current knowledge and emphasize key processes, this manuscript focuses on three exemplary networks, in which Notch family members promote BC aggressiveness through interactions with pro-inflammatory elements: (1) Cross-talks of the Notch pathway with myeloid cells that contribute to cancer-related inflammation, with macrophages; (2) Cross-talks of the Notch pathway with pro-inflammatory soluble mediators, interleukin 6 (IL-6) and IL-6-driven pathways (through the transcription factor signal transducer and activator of transcription 3, STAT3);. (3) Cross-talks of the Notch pathway with transcription factors that promote inflammatory processes, mainly nuclear factor-kappaB (NF-κB) Following these three sections, we conclude this article by discussing the implications of Notch-inflammation interplays in cancer research and therapy, in BC and in general
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
