乳腺癌（BC）是女性恶性肿瘤的主要致病因素和第二主要死因。尽管目前已批准针对乳腺癌亚型（ER阳性、HER2阳性）的药物，但转移性乳腺癌或缺乏靶向的三阴性乳腺癌仍缺乏有效的靶向药物或治疗策略。因此，发现新的潜在靶点刻不容缓。ERCC6L 是参与细胞有丝分裂过程中染色体分离的重要蛋白质。然而，ERCC6L 在乳腺癌的发生和进展中的作用尚不清楚。本研究发现，ERCC6L 在乳腺癌中高度表达，尤其是在三阴性乳腺癌（TNBC）中，与患者不良预后密切相关。本研究首次建立了 ERCC6L 有条件敲除小鼠模型，并证实了 ERCC6L 对乳腺组织发育和乳腺癌的发生和进展必不可少。在体外细胞培养中，ERCC6L 在乳腺癌恶性进展中起到肿瘤促进剂的作用。过表达 ERCC6L 促进细胞增殖、迁移和侵袭，而 ERCC6L 敲低导致相反的结果。从机制上讲，ERCC6L 通过调节 G2/M 检查点信号通路加速细胞周期。此外，我们证明了 ERCC6L 和 KIF4A 之间存在相互作用，两者都是有丝分裂中密切相关的因子，并参与乳腺癌的恶性进展。我们首次证明，ERCC6L 缺失可以显著抑制乳腺组织肿瘤的发生和发展。ERCC6L 被发现通过调节 p53/p21/CDK1/Cyclin B 和 PLK/CDC25C/CDK1/Cyclin B 信号通路来加速细胞周期，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，两者都与有丝分裂密切相关，并对乳腺肿瘤的生长和转移起到贡献。总之，我们的结果表明 ERCC6L 可能作为 BC 治疗的有希望的靶点。© 2023. 意大利国立癌症研究所 "Regina Elena"。

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 G2/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.© 2023. Italian National Cancer Institute ‘Regina Elena’.