NF-κB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype.
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.
Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
Mizuki
M
Yamamoto
Yuu
Y
Taguchi
Taku
T
Ito-Kureha
Kentaro
K
Semba
Noritaka
N
Yamaguchi
Jun-ichiro
J
Inoue
D002135:Calcium-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism; D002280:Basal Cell Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D000097782:NF-kappaB-Inducing Kinase; C000606273:JAG1 protein, human