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

• Published in: Nature communications Vol. 4; no. 1; p. 2299
• Main Authors: Yamamoto, Mizuki, Taguchi, Yuu, Ito-Kureha, Taku, Semba, Kentaro, Yamaguchi, Noritaka, Inoue, Jun-ichiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2013
• Subjects: 631/250/516/1909; 631/67/1347; 631/67/71; Calcium-Binding Proteins - biosynthesis; Calcium-Binding Proteins - metabolism; Carcinoma, Basal Cell - metabolism; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Intercellular Signaling Peptides and Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - metabolism; Jagged-1 Protein; Membrane Proteins - biosynthesis; Membrane Proteins - metabolism; multidisciplinary; Neoplasm Recurrence, Local - metabolism; Neoplastic Stem Cells - metabolism; NF-kappa B - metabolism; NF-kappaB-Inducing Kinase; Protein Serine-Threonine Kinases - biosynthesis; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Receptors, Notch - metabolism; RNA Interference; RNA, Small Interfering; Science; Science (multidisciplinary); Serrate-Jagged Proteins; Signal Transduction; Triple Negative Breast Neoplasms - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3299

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. Aggressive types of breast cancer often exhibit constitutive activation of the pro-inflammatory transcription factor NF-κB. Here, Yamamoto et al . show that, in basal-like breast cancer, NF-κB upregulates the Notch receptor ligand JAG1 in non-cancer stem cells and thereby induces proliferation of breast cancer stem cells.