Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70401, Taiwan.
Division of General Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, 813414, Taiwan.
Cancer Gene Ther. 2023 Mar;30(3):404-413. doi: 10.1038/s41417-022-00559-x. Epub 2022 Nov 18.
Currently, the survival rate for breast cancer is more than 90%, but once the cancer cells metastasize to distal organs, the survival rate is dramatically reduced, to less than 30%. Triple-negative breast cancer accounts for 15-20% of all breast cancers. Triple-negative breast cancer (TNBC) is associated with poor prognostic and diagnostic outcomes due to the limiting therapeutic strategies, relative to non-TNBC breast cancers. Therefore, the development of targeted therapy for TNBC metastasis remains an urgent issue. In this study, high Carboxyl-terminal modulator protein (CTMP) is significantly associated with recurrence and disease-free survival rate in TNBC patients. Overexpression of CTMP promotes migration and invasion abilities in BT549 cells. Down-regulating of CTMP expression inhibits migration and invasion abilities in MDA-MB-231 cells. In vivo inoculation of high-CTMP cells enhances distant metastasis in mice. The metastasis incidence rate is decreased in mice injected with CTMP-downregulating MDA-MB-231 cells. Gene expression microarray analysis indicates the Akt-dependent pathway is significantly enhanced in CTMP overexpressing cells compared to the parental cells. Blocking Akt activation via Akt inhibitor treatment or co-expression of the dominant-negative form of Akt proteins successfully abolishes the CTMP mediating invasion in TNBC cells. Our findings suggest that CTMP is a potential diagnostic marker for recurrence and poor disease-free survival in TNBC patients. CTMP promotes TNBC metastasis via the Akt-activation-dependent pathway.
目前，乳腺癌的存活率超过 90%，但一旦癌细胞转移到远端器官，存活率就会显著降低，低于 30%。三阴性乳腺癌占所有乳腺癌的 15-20%。由于治疗策略有限，三阴性乳腺癌（TNBC）与预后和诊断结果较差相关，与非 TNBC 乳腺癌相比。因此，开发针对 TNBC 转移的靶向治疗仍然是一个紧迫的问题。在这项研究中，高羧基末端调节剂蛋白（CTMP）与 TNBC 患者的复发和无病生存率显著相关。CTMP 的过表达促进了 BT549 细胞的迁移和侵袭能力。下调 CTMP 表达抑制了 MDA-MB-231 细胞的迁移和侵袭能力。高 CTMP 细胞的体内接种增强了小鼠的远处转移。注射 CTMP 下调 MDA-MB-231 细胞的小鼠转移发生率降低。基因表达微阵列分析表明，与亲本细胞相比，CTMP 过表达细胞中 Akt 依赖性途径显著增强。通过 Akt 抑制剂处理或 Akt 蛋白显性失活形式的共表达阻断 Akt 激活可成功消除 CTMP 在 TNBC 细胞中介导的侵袭。我们的研究结果表明，CTMP 是 TNBC 患者复发和无病生存率低的潜在诊断标志物。CTMP 通过 Akt 激活依赖性途径促进 TNBC 转移。
