The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China.
Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
J Exp Clin Cancer Res. 2023 Sep 4;42(1):227. doi: 10.1186/s13046-023-02806-x.
Breast cancer (BC) is the leading cause of morbidity and the second leading cause of death among female malignant tumors. Although available drugs have been approved for the corresponding breast cancer subtypes (ER-positive, HER2) currently, there are still no effective targeted drugs or treatment strategies for metastatic breast cancer or triple-negative breast cancer that lack targets. Therefore, it is urgent to discover new potential targets. ERCC6L is an essential protein involved in chromosome separation during cell mitosis. However, the effect of ERCC6L on the tumorigenesis and progression of breast cancer is unclear.
Here, we found that ERCC6L was highly expressed in breast cancer, especially in TNBC, which was closely related to poor outcomes of patients. An ERCC6L conditional knockout mouse model was first established in this study, and the results confirmed that ERCC6L was required for the development of the mammary gland and the tumorigenesis and progression of mammary gland cancers. In in vitro cell culture, ERCC6L acted as a tumor promoter in the malignant progression of breast cancer cells. Overexpression of ERCC6L promoted cell proliferation, migration and invasion, while knockdown of ERCC6L caused the opposite results. Mechanistically, ERCC6L accelerated the cell cycle by regulating the G/M checkpoint signalling pathway. Additionally, we demonstrated that there is an interaction between ERCC6L and KIF4A, both of which are closely related factors in mitosis and are involved in the malignant progression of breast cancer.
We first demonstrated that ERCC6L deficiency can significantly inhibit the occurrence and development of mammary gland tumors. ERCC6L was found to accelerate the cell cycle by regulating the p53/p21/CDK1/Cyclin B and PLK/CDC25C/CDK1/Cyclin B signalling pathways, thereby promoting the malignant progression of breast cancer cell lines. There was a direct interaction between KIF4A and ERCC6L, and both are closely associated with mitosis and contribute to growth and metastasis of breast tumor. To sum up, our results suggest that ERCC6L may be used as a promising target for the treatment of BC.
乳腺癌（BC）是女性恶性肿瘤发病率的主要原因，也是女性恶性肿瘤死亡的第二大原因。尽管目前已有针对相应乳腺癌亚型（ER 阳性、HER2）的可用药物获得批准，但对于缺乏靶点的转移性乳腺癌或三阴性乳腺癌，仍然没有有效的靶向药物或治疗策略。因此，迫切需要发现新的潜在靶点。ERCC6L 是细胞有丝分裂过程中染色体分离所必需的一种关键蛋白。然而，ERCC6L 对乳腺癌的发生和发展的影响尚不清楚。
在这里，我们发现 ERCC6L 在乳腺癌中高度表达，尤其是在三阴性乳腺癌中，与患者的不良预后密切相关。本研究首次建立了 ERCC6L 条件性敲除小鼠模型，结果证实 ERCC6L 是乳腺发育以及乳腺肿瘤发生和发展所必需的。在体外细胞培养中，ERCC6L 在乳腺癌细胞的恶性进展中充当肿瘤促进因子。过表达 ERCC6L 促进细胞增殖、迁移和侵袭，而敲低 ERCC6L 则产生相反的结果。从机制上讲，ERCC6L 通过调节 G/M 检查点信号通路加速细胞周期进程。此外，我们证明 ERCC6L 与 KIF4A 之间存在相互作用，这两种蛋白都是有丝分裂过程中的密切相关因子，并且都参与了乳腺癌的恶性进展。
我们首次证明 ERCC6L 缺乏可显著抑制乳腺肿瘤的发生和发展。发现 ERCC6L 通过调节 p53/p21/CDK1/Cyclin B 和 PLK/CDC25C/CDK1/Cyclin B 信号通路加速细胞周期进程，从而促进乳腺癌细胞系的恶性进展。KIF4A 和 ERCC6L 之间存在直接相互作用，这两种蛋白都与有丝分裂密切相关，有助于乳腺癌的生长和转移。综上所述，我们的研究结果表明 ERCC6L 可能成为治疗 BC 的一个有前途的靶点。
