众所周知，缺乏雌激素受体、孕激素受体、人类表皮生长因子受体2（HER2）的三阴性乳腺癌由于肿瘤生物学恶性程度较高且治疗选择有限而预后不佳。极光激酶是细胞有丝分裂过程蛋白质丝氨酸苏氨酸激酶之一，包括极光激酶A、极光激酶B、极光激酶C，可以调节有丝分裂和减数分裂，其基因突变或过表达可以引起细胞癌变。极光激酶A失调以及哺乳动物雷帕霉素靶蛋白（mTOR）信号转导通路过度活化通常发生于多种癌症类型。既往研究已经发现，极光激酶A可以激活mTOR信号转导通路并且抑制乳腺癌细胞自噬活性。不过，极光激酶A是否以及如何调节三阴性乳腺癌的mTOR信号转导通路尚不明确。
8月13日，英国《自然》旗下《细胞死亡与疾病》在线发表南昌大学第一附属医院、华中科技大学同济医学院附属同济医院、南昌市第三医院（江西乳腺专科医院）、陆军军医大学（第三军医大学）第二附属医院（重庆新桥医院）、密歇根大学、中山大学附属第一医院的研究报告，发现极光激酶A通过细胞外信号调节激酶（ERK）1/2对mTOR信号转导通路进行调节，可以促进三阴性乳腺癌的肿瘤生长和转移，而双重靶向极光激酶A和mTOR可以协同抑制三阴性乳腺癌。
该研究发现极光激酶A和磷酸化mTOR高表达于三阴性乳腺癌的细胞和组织，并且表达水平互相成正比。抑制极光激酶A或者阻止其编码基因表达，可以减少磷酸化mTOR并且抑制三阴性乳腺癌的细胞繁殖和转移，而极光激酶A过表达可以增加磷酸化mTOR水平并且促进三阴性乳腺癌细胞的繁殖和转移，该作用可以通过同时干扰mTOR而被显着减弱。有趣的是，极光激酶A过表达可以增强磷酸化mTOR和磷酸化ERK1/2表达，而干扰或抑制ERK1/2可以阻断极光激酶A诱发磷酸化mTOR。不过，干扰或抑制mTOR未能逆转极光激酶A诱发ERK1/2，表明极光激酶A→ERK1/2→mTOR对于三阴性乳腺癌可以形成致癌连锁反应。极光激酶A和mTOR双重抑制对于三阴性乳腺癌细胞株和异种移植模型可以产生显着的协同作用。
因此，该研究结果表明，极光激酶A和mTOR有望成为三阴性乳腺癌的潜在治疗靶点。
Cell Death Dis. Aug 13. [Epub ahead of print]
Aurora-A/ERK1/2/mTOR axis promotes tumor progression in triple-negative breast cancer and dual-targeting Aurora-A/mTOR shows synthetic lethality.
Wenfeng Zhang, Ding Xia, Zhangyun Li, Tao Zhou, Tingting Chen, Zhengping Wu, Weihua Zhou, Zilun Li, Longkun Li, Jie Xu.
First Affiliated Hospital, Nanchang University, Nanchang, China; Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Third Hospital of Nangchang, Nanchang, China; Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, China; University of Michigan, Ann Arbor, MI, USA; First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Triple-negative breast cancer (TNBC), defined as a tumor subtype that lacks ER, PR, and HER2, shows a poor prognosis due to its aggressive tumor biology and limited treatment options. Deregulation of Aurora kinase A (Aur-A), a member of the mitotic serine/threonine Aurora kinase family, and overactivation of the mTOR pathway commonly occur in multiple cancer types. We previously found that Aur-A activated the mTOR pathway and inhibited autophagy activity in breast cancer cell models. Whether and how Aur-A regulates mTOR in TNBC are still unclear. Here, we found that Aur-A and p-mTOR are highly expressed and positively associated with each other in TNBC cells and tissues. Inhibition or knockdown of Aur-A decreased p-mTOR and suppressed cell proliferation and migration, whereas overexpression of Aur-A increased p-mTOR levels and promoted cell proliferation and migration, which was significantly abrogated by simultaneous silencing of mTOR. Intriguingly, overexpression of Aur-A enhanced the expression of p-mTOR and p-ERK1/2, and silencing or inhibition of ERK1/2 blocked Aur-A-induced p-mTOR. However, silencing or inhibition of mTOR failed to reverse Aur-A-induced ERK1/2, indicating that Aur-A/ERK1/2/mTOR forms an oncogenic cascade in TNBC. We finally found that double inhibition of Aur-A and mTOR showed significant synergistic effects in TNBC cell lines and a xenograft model, indicating that Aur-A and mTOR are potential therapeutic targets in the TNBC subtype.
DOI: 10.1038/s41419-019-1855-z
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