Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Pharmacology, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, 518055, China.
State Key Laboratory of Oncology in South China, Department of Medical Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
Oncogene. 2020 Mar;39(12):2550-2567. doi: 10.1038/s41388-020-1165-z. Epub 2020 Jan 29.
Aurora B is a serine/threonine kinase that has been implicated in regulating cell proliferation in distinct cancers, including breast cancer. Here we show that Aurora B expression is elevated in basal-like breast cancer (BLBC) compared with other breast cancer subtypes. This high level of expression seems to correlate with poor metastasis-free survival and relapse-free survival in affected patients. Mechanistically, we show that elevated Aurora B expression in breast cancer cells activates AKT/GSK3β to stabilize Snail1 protein, a master regulator of epithelial-mesenchymal transition (EMT), leading to EMT induction in a kinase-dependent manner. Conversely, Aurora B knock down by short-hairpin RNAs (shRNAs) suppresses AKT/GSK3β/Snail1 signaling, reverses EMT and reduces breast cancer metastatic potential in vitro and in vivo. Finally, we identified a specific OCT4 phosphorylation site (T343) responsible for mediating Aurora B-induced AKT/GSK3β/Snail1 signaling and EMT that could be attenuated by Aurora B kinase inhibitor treatment. These findings support that Aurora B induces EMT to promote breast cancer metastasis via OCT4/AKT/GSK3β/Snail1 signaling. Pharmacologic Aurora B inhibition might be a potential effective treatment for breast cancer patients with metastatic disease.
极光 B 是一种丝氨酸/苏氨酸激酶，已被牵连到调节不同癌症中的细胞增殖，包括乳腺癌。在这里，我们表明，与其他乳腺癌亚型相比，基底样乳腺癌（BLBC）中极光 B 的表达升高。这种高表达水平似乎与受影响患者的无转移生存和无复发生存率较差相关。从机制上讲，我们表明乳腺癌细胞中极光 B 的高表达激活 AKT/GSK3β 以稳定 Snail1 蛋白，Snail1 蛋白是上皮-间充质转化（EMT）的主要调节剂，导致 EMT 以激酶依赖性方式诱导。相反，短发夹 RNA（shRNA）敲低极光 B 抑制 AKT/GSK3β/Snail1 信号通路，逆转 EMT，并降低体外和体内乳腺癌的转移潜能。最后，我们确定了一个特定的 OCT4 磷酸化位点（T343），该位点负责介导极光 B 诱导的 AKT/GSK3β/Snail1 信号通路和 EMT，该信号通路可被极光 B 激酶抑制剂治疗减弱。这些发现支持极光 B 通过 OCT4/AKT/GSK3β/Snail1 信号通路诱导 EMT 来促进乳腺癌转移。极光 B 抑制药理学可能是治疗转移性乳腺癌患者的一种潜在有效方法。
