NF-κB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype

Abstract

Patients with triple-negative breast cancer display the highest rates of early relapse of all patients with breast cancer. The basal-like subtype, a subgroup of triple-negative breast cancer, exhibits high levels of constitutively active NF-κB signalling. Here we show that NF-κB activation, induced by inflammatory cytokines or by epigenetically dysregulated NIK expression, cell-autonomously upregulates JAG1 expression in non-cancer stem cells. This upregulation stimulates NOTCH signalling in cancer stem cells in trans, leading to an expansion of cancer stem cell populations. Among breast cancers, the NF-κB-dependent induction of JAG1 and the NOTCH-dependent expansion of the cancer stem cell population occur only in the basal-like subtype. Collectively, our results indicate that NF-κB has a non-cell-autonomous role in regulating cancer stem cell populations by forming intratumoural microenvironments composed of JAG1-expressing non-cancer stem cells with a basal-like subtype.

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

“…NF-jB is constitutively activated in BT-474-R Although NF-kB is known to be activated in basal-like (26) and drug-resistant HER2+ tumor cells, (27) it is not known whether NF-kB is activated in TZR HER2+ tumor cells. (28,29) The fact that HER2 expression is unaltered between BT-474 and BT-474-R suggests that there might be alternate pathways.…”

Tópicos em sinalização celular e bioinformática: Princípios de funcionamento do circuito de sinalização Notch e aprendizagem supervisionada variacional de relevância

“…This phenomenon, also known as lateral induction, can also play a crucial role in generating spatial patterns with wavelength of a dozen of cells [64], and can thereby facilitate the spatial patterning of different cell types required during pancreatic development [65]. However, since the previous computational models for lateral induction do not specifically consider Jagged, they can offer limited insights into cases where Jagged plays a key role, such as in tumor-stroma crosstalk [33,27]. 2.1.3 Notch-Delta-Jagged (NDJ) circuit: a three-way switch.…”

“…Transition (EMT) [73]. Jagged1 can also induce the expression of NF-kB [74], which can increase the population of CSCs and further increase the secretion of Jagged1 [33], suggesting a wave-like mechanism in the tumor microenvironment to rake up the production and maintenance of therapy-resistant CSCs. Future theoretical studies of these circuits hold promise for appreciating the key role of soluble Jagged1 in mediating two interlinked and clinically insuperable facets of cancer -metastasis (as a result of cells undergoing EMT) and tumor relapse (as a result of expanded CSC pool).…”

“…In addition to transmembrane ligands, Notch signaling can also be activated by soluble forms of the ligands [33,27,28]. Transition (EMT) [73].…”

“…It also facilitates the colonization of the Circulating Tumor Cells (CTCs) by enabling cell-cell communication between CTCs and the cells of the organ where they settle down and develop metastases [31,9] that causes more than 90% of cancer-related deaths [32]. Furthermore, Notch-Jagged signaling can also maintain and/or expand the population of Cancer Stem Cells -highly plastic cancer cells that can initiate a new tumor [33,27], thereby promoting tumor relapse. Notably, Notch-Jagged signaling also plays a crucial role in angiogenesis [34], cancer metastasis [9], and rapid development of cancer chemotherapy and radiation therapy resistance [35].…”