To improve cancer patient outcome significantly, we must understand the mechanisms regulating stem-like cancer cells, which have been implicated as a cause of metastasis and treatment resistance. The transcription factor C/EBPδ can exhibit pro- and anti-tumorigenic activities, but the mechanisms underlying the complexity of its functions are poorly understood. Here we identify a role for breast cancer cell intrinsic C/EBPδ in promoting phenotypes that have been associated with cancer stem cells (CSCs). While C/EBPδ expression is not abundant in most metastatic breast cancers, our data support a pro-tumorigenic role of C/EBPδ when expressed in subsets of tumor cells and/or through transient activation by the tumor microenvironment or loss of substrate adhesion. Using genetic mouse models and human breast cancer cell lines, we show that deletion or depletion of C/EBPδ reduced expression of stem cell factors and stemnness markers, sphere formation and self-renewal, along with growth of tumors and established experimental metastases in vivo. C/EBPδ is also known as a mediator of the innate immune response, which is enhanced by hypoxia and interleukin-6 (IL-6) signaling, two conditions that also play important roles in cancer progression. Our mechanistic data reveal C/EBPδ as a link that engages two positive feedback loops, in part by directly targeting the IL-6 receptor (IL6RA) gene, and, thus, amplifying IL-6 and HIF-1 signaling. This study provides a molecular mechanism for the synergism of tumor microenvironmental conditions in cancer progression with potential implications for the targeting of CSCs.

中文翻译：

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C/EBPδ 连接 IL-6 和 HIF-1 信号传导以促进乳腺癌干细胞相关表型。


为了显着改善癌症患者的治疗效果，我们必须了解干细胞样癌细胞的调节机制，这些细胞被认为是转移和治疗抵抗的原因。转录因子 C/EBPδ 可以表现出促肿瘤和抗肿瘤活性，但其功能复杂性背后的机制尚不清楚。在这里，我们确定了乳腺癌细胞内在 C/EBPδ 在促进与癌症干细胞 (CSC) 相关的表型中的作用。虽然 C/EBPδ 在大多数转移性乳腺癌中表达并不丰富，但我们的数据支持当 C/EBPδ 在肿瘤细胞亚群中表达和/或通过肿瘤微环境的瞬时激活或基质粘附丧失时，C/EBPδ 具有促肿瘤作用。使用遗传小鼠模型和人类乳腺癌细胞系，我们发现 C/EBPδ 的缺失或耗尽会降低干细胞因子和干细胞标记物的表达、球体形成和自我更新，以及肿瘤的生长和体内实验性转移的建立。 C/EBPδ 也被认为是先天免疫反应的介质，缺氧和白细胞介素 6 (IL-6) 信号传导会增强先天免疫反应，这两种条件在癌症进展中也发挥着重要作用。我们的机制数据揭示了 C/EBPδ 作为一个参与两个正反馈环的链接，部分是通过直接靶向 IL-6 受体 (IL6RA) 基因，从而放大 IL-6 和 HIF-1 信号传导。这项研究提供了肿瘤微环境条件在癌症进展中协同作用的分子机制，对 CSC 的靶向具有潜在影响。