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.
Nat Commun. 2013;4:2299. 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.
三阴性乳腺癌患者的复发率在所有乳腺癌患者中最高。基底样亚型是三阴性乳腺癌的一个亚组，表现出 NF-κB 信号的持续激活。在这里，我们表明 NF-κB 的激活，由炎症细胞因子诱导或由表观遗传失调的 NIK 表达诱导，细胞自主地上调非癌干细胞中 JAG1 的表达。这种上调在转位中刺激癌症干细胞中的 NOTCH 信号，导致癌症干细胞群体的扩增。在乳腺癌中，NF-κB 依赖性 JAG1 的诱导和 NOTCH 依赖性癌症干细胞群体的扩增仅发生在基底样亚型中。总之，我们的结果表明，NF-κB 通过形成由基底样亚型表达 JAG1 的非癌干细胞组成的肿瘤内微环境，在调节癌症干细胞群体方面具有非细胞自主的作用。
