地塞米松等糖皮质激素是最常用的免疫抑制剂之一，还被广泛用于减轻恶心、呕吐、水肿、过敏等紫杉醇化疗药物副作用和晚期癌症症状。不过，作为双刃剑，地塞米松等糖皮质激素既可抑制淋巴瘤等血液系统恶性肿瘤和膀胱癌的生长，又可促进结肠癌等恶性肿瘤的转移，对乳腺癌的影响及其具体机制尚不明确。此外，近期研究表明，部分乳腺癌患者接受紫杉醇化疗后发生转移，紫杉醇也有双刃剑的作用，对癌细胞既有细胞毒作用，又有促转移作用，既往研究大多针对紫杉醇本身，极少针对紫杉醇辅助用药。
2021年7月16日，英国《自然》旗下《肿瘤基因》在线发表四川大学华西医院、苏州信达生物、中国科学院的研究报告，探讨了地塞米松对小鼠乳腺癌转移模型的影响及其具体机制。
该研究首先利用小鼠三阴性乳腺癌细胞4T1、人类激素受体阳性乳腺癌胸水转移细胞MCF-7、人类三阴性乳腺癌胸水转移细胞MDA-MB-231、人类乳腺导管癌腹水转移细胞ZR-75-30建立4种小鼠乳腺癌转移模型，探讨地塞米松促进乳腺癌细胞迁移的分子机制，同时探讨地塞米松＋紫杉醇化疗对乳腺癌肺转移的影响。
结果证实，地塞米松可直接促进小鼠4T1乳腺癌肺转移，即使对于免疫缺陷小鼠，表明地塞米松的促转移作用与免疫抑制能力无关。糖皮质激素受体抑制剂米非司酮可显著抑制地塞米松对乳腺癌细胞的促转移作用，尤其对于4T1、MDA-MB-231、ZR-75-30细胞。
机制分析表明，地塞米松促转移作用由肿瘤细胞糖皮质激素受体→磷脂酰肌醇激酶PI3K→血清糖皮质激素诱导激酶SGK1→结缔组织生长因子CTGF信号通路传导。当地塞米松结合肿瘤细胞糖皮质激素受体，可激活PI3K信号通路并增加SGK1表达，随后通过泛素蛋白连接酶NEDD4L→转录因子SMAD2增加CTGF表达。
此外，对于紫杉醇＋地塞米松治疗乳腺癌的标准方案，地塞米松是肺转移的主要因素，而且用SGK1抑制剂可显著减少肺转移。
因此，该研究结果表明，地塞米松可诱发乳腺癌转移，SGK1有望成为防治乳腺癌转移的新靶点，尤其对于主要依靠紫杉醇化疗的三阴性乳腺癌，故有必要进一步开展临床研究进行验证。
Oncogene. 2021 Jul 16. Online ahead of print.
Dexamethasone enhances the lung metastasis of breast cancer via a PI3K-SGK1-CTGF pathway.
Zhang Y, Shi G, Zhang H, Xiong Q, Cheng F, Wang H, Luo J, Zhang Y, Shi P, Xu J, Fu J, Chen N, Cheng L, Li Y, Dai L, Yang Y, Yu D, Zhang S, Deng H.
West China Hospital, Sichuan University, Chengdu, China; Innovent Biologics, Inc, Suzhou, Jiangsu, China; Chinese Academy of Medical Sciences, Beijing, China.
Dexamethasone (Dex), as a pretreatment agent, is widely used to attenuate the side effects of chemotherapy in breast cancer treatment. However, whether and how Dex affects breast cancer metastasis remain to be furtherly understood. In this study, we established several mouse breast cancer metastatic models to study the effect of Dex in vitro and in vivo. Transwell, Western Blot and RNA interference were applied to study the molecular mechanism of Dex in promoting breast cancer cell migration. Meanwhile, the effect of Dex on lung metastasis of breast cancer in Dex combined with PTX chemotherapy was discussed. Our results confirmed that Dex could promote breast cancer cell metastasis both in vitro and in vivo. Mechanistic studies revealed that this pro-metastatic effect of Dex was mediated by the GR-PI3K-SGK1-CTGF pathway in tumor cells. Ligation of Dex and glucocorticoid receptor (GR) on tumor cells activated the PI3K signaling pathway and upregulated serum glucocorticoid-inducible kinase 1 (SGK1) expression, and then increased the expression of connective tissue growth factor (CTGF) through Nedd4l-Smad2. Moreover, Dex was the leading factor for lung metastasis in a standard regimen for breast cancer treatment with paclitaxel and Dex. Importantly, targeting SGK1 with the inhibitor GSK650394 remarkably reduced lung metastasis in this regimen. Our present data provide new insights into Dex-induced breast cancer metastasis and indicate that SGK1 could be a candidate target for the treatment of breast cancer metastasis.
PMID: 34272474
DOI: 10.1038/s41388-021-01944-w
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