Sperm-associated antigen 5 (SPAG5) is an important driver of the cell mitotic spindle required for chromosome segregation and progression into anaphase. SPAG5 has been identified as an important proliferation marker and chemotherapy-sensitivity predictor, especially in estrogen receptor-negative breast cancer subtypes. Here, we report that SPAG5 is a direct target of miR-10b-3p, and its aberrantly high expression associates with poor disease-free survival in two large cohorts of breast cancer patients. SPAG5 depletion strongly impaired cancer cell cycle progression, proliferation, and migration. Interestingly, high expression of SPAG5 pairs with a YAP/TAZ-activated signature in breast cancer patients. Reassuringly, the depletion of YAP, TAZ, and TEAD strongly reduced SPAG5 expression and diminished its oncogenic effects. YAP, TAZ coactivators, and TEAD transcription factors are key components of the Hippo signaling pathway involved in tumor initiation, progression, and metastasis. Furthermore, we report that SPAG5 is a direct transcriptional target of TEAD/YAP/TAZ, and pharmacological targeting of YAP and TAZ severely reduces SPAG5 expression. Collectively, our data uncover an oncogenic feedback loop, comprising miR-10b-3p, SPAG5, and YAP/TAZ/TEAD, which fuels the aberrant proliferation of breast cancer.

精子相关抗原 5 (SPAG5) 是染色体分离和进入后期所需的细胞有丝分裂纺锤体的重要驱动因素。SPAG5 已被确定为重要的增殖标志物和化疗敏感性预测因子，尤其是在雌激素受体阴性乳腺癌亚型中。在这里，我们报告 SPAG5 是 miR-10b-3p 的直接靶标，其异常高表达与两个大型乳腺癌患者队列中较差的无病生存期相关。SPAG5 耗竭严重损害癌细胞周期进程、增殖和迁移。有趣的是，在乳腺癌患者中，SPAG5 的高表达与 YAP/TAZ 激活的特征配对。令人欣慰的是，YAP、TAZ 和 TEAD 的消耗大大降低了 SPAG5 的表达并降低了其致癌作用。YAP、TAZ 共激活剂，和 TEAD 转录因子是参与肿瘤起始、进展和转移的 Hippo 信号通路的关键组分。此外，我们报告 SPAG5 是 TEAD/YAP/TAZ 的直接转录靶标，YAP 和 TAZ 的药理学靶向严重降低 SPAG5 表达。总的来说，我们的数据揭示了一个致癌反馈回路，包括 miR-10b-3p、SPAG5 和 YAP/TAZ/TEAD，它促进了乳腺癌的异常增殖。