Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy.
Regina Elena National Cancer Institute, Rome, Italy.
Cancer Res. 2017 Jun 15;77(12):3268-3279. doi: 10.1158/0008-5472.CAN-16-3126. Epub 2017 Apr 11.
The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptor-positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4Rα antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44/CD24 cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-κB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFNγ-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies. .
肿瘤微环境提供促炎细胞因子，有利于癌症细胞生长和侵袭行为的许可环境。在这里，我们展示了脂肪组织和雌激素受体阳性及三阴性乳腺癌细胞类型分泌的 IL4 如何促进乳腺癌的进展。用 IL4Rα 拮抗剂 IL4DM 阻断自分泌和旁分泌 IL4 信号会通过下调 MAPK 通路活性来损害乳腺癌细胞的增殖、侵袭和肿瘤生长。IL4DM 通过抑制 NF-κB 减少 CD44/CD24 癌症干细胞样细胞的数量，并上调双特异性磷酸酶 DUSP4 的表达。通过强制表达 DUSP4，将转移性细胞转化为非转移性细胞。从机制上讲，通过 RNAi 介导的 DUSP4 衰减激活了 ERK 和 p38 MAPK 通路，增加了干细胞样特性，并产生了转移性能力。靶向 IL4 信号会通过增加 IFNγ 阳性 CTL 的数量来增强对乳腺癌细胞的抗癌治疗和免疫反应。我们的研究结果表明了 IL4 在促进乳腺癌侵袭性方面的作用，以及靶向它可能如何提高现有治疗方法的疗效。
