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Notch-Inflammation Networks in Regulation of Breast Cancer Progression.

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-?B. 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.

SUBMITTER: Liubomirski Y

PROVIDER: S-EPMC7407628 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Notch-Inflammation Networks in Regulation of Breast Cancer Progression.

Liubomirski Yulia Y Ben-Baruch Adit A

Cells 20200628 7

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 ca ...[more]

PMID: 32605277

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Project description:Stromal cells and pro-inflammatory cytokines play key roles in promoting the aggressiveness of triple-negative breast cancers (TNBC; Basal/Basal-like). In our previous study we demonstrated that stimulation of TNBC and mesenchymal stem cells (MSCs) co-cultures by the pro-inflammatory cytokine tumor necrosis factor α (TNFα) has led to increased metastasis-related properties in vitro and in vivo. In this context, elevated release of the pro-metastatic chemokines CXCL8 (IL-8) and CCL5 (RANTES) was noted in TNFα- and interleukin-1β (IL-1β)-stimulated TNBC:MSC co-cultures; the process was partly (CXCL8) and entirely (CCL5) dependent on physical contacts between the two cell types. Here, we demonstrate that DAPT, inhibitor of γ-secretase that participates in activation of Notch receptors, inhibited the migration and invasion of TNBC cells that were grown in "Contact" co-cultures with MSCs or with patient-derived cancer-associated fibroblasts (CAFs), in the presence of TNFα. DAPT also inhibited the contact-dependent induction of CXCL8, but not of CCL5, in TNFα- and IL-1β-stimulated TNBC:MSC/CAF co-cultures; some level of heterogeneity between the responses of different TNBC cell lines was noted, with MDA-MB-231:MSC/CAF co-cultures being the most sensitive to DAPT. Patient dataset studies comparing basal tumors to luminal-A tumors, and mRNA analyses of Notch receptors in TNBC and luminal-A cells pointed at Notch1 as possible mediator of CXCL8 increase in TNFα-stimulated TNBC:stroma "Contact" co-cultures. Accordingly, down-regulation of Notch1 in TNBC cells by siRNA has substantially reduced the contact-dependent elevation in CXCL8 in TNFα- and also in IL-1β-stimulated TNBC:MSC "Contact" co-cultures. Then, studies in which CXCL8 or p65 (NF-κB pathway) were down-regulated (siRNAs; CRISPR/Cas9) in TNBC cells and/or MSCs, indicated that upon TNFα stimulation of "Contact" co-cultures, p65 was activated and led to CXCL8 production mainly in TNBC cells. Moreover, our findings indicated that when tumor cells interacted with stromal cells in the presence of pro-inflammatory stimuli, TNFα-induced p65 activation has led to elevated Notch1 expression and activation, which then gave rise to elevated production of CXCL8. Overall, tumor:stroma interactions set the stage for Notch1 activation by pro-inflammatory signals, leading to CXCL8 induction and consequently to pro-metastatic activities. These observations may have important clinical implications in designing novel therapy combinations in TNBC.

Dataset Information

Notch-Inflammation Networks in Regulation of Breast Cancer Progression.

Publications

Notch-Inflammation Networks in Regulation of Breast Cancer Progression.

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