Ning Bohan, Liu Chang, Kucukdagli Ali Cem, Zhang Jiuyi, Jing Han, Zhou Zhiqian, Zhang Yuwei, Dong Ying, Chen Yunjia, Guo Hua, Xu Jia
Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, 720 20th Street South, Birmingham, AL, 35294, USA.
Sci Rep. 2025 Jan 25;15(1):3211. doi: 10.1038/s41598-025-87315-x.
Nowadays, chemotherapy and immunotherapy remain the major treatment strategies for Triple-Negative Breast Cancer (TNBC). Identifying biomarkers to pre-select and subclassify TNBC patients with distinct chemotherapy responses is essential. In the current study, we performed an unbiased Reverse Phase Protein Array (RPPA) on TNBC cells treated with chemotherapy compounds and found a leading significant increase of phosphor-AURKA/B/C, AURKA, AURKB, and PLK1, which fall into the mitotic kinase group. The increase of AURKA and AURKB protein was majorly due to a post-transcription level regulation, and Paclitaxel treatment induced Aurora Kinases protein phosphorylation on AURKA(T288)/AURKB(T232) sites and their protein stability. In our UAB TNBC cohort, the expression of AURKA and AURKB was significantly higher in TNBC tumors compared to normal adjacent tissues, and AURKB was found to be highly expressed in African American TNBC patients compared to European Americans. Moreover, Aurora Kinases overexpression in TNBC cells renders resistance to Paclitaxel treatment and attenuates the apoptosis effect triggered by chemotherapy treatment, suggesting Aurora Kinases could mediate the chemo-resistance in TNBC. Hence, a combination of Aurora kinase inhibitors or PROTAC degrader and taxane-type chemotherapy significantly enhanced the chemotherapy effect. In summary, we revealed that Aurora Kinases upregulation after treatment with chemotherapy could confer chemotherapy resistance to TNBC cells, and AURKB could serve as preselection markers for stratifying patients' response to neoadjuvant chemotherapy.
如今，化疗和免疫疗法仍然是三阴性乳腺癌（TNBC）的主要治疗策略。识别生物标志物以预先选择TNBC患者并根据不同的化疗反应进行亚分类至关重要。在本研究中，我们对经化疗化合物处理的TNBC细胞进行了无偏倚的反相蛋白质阵列（RPPA）分析，发现属于有丝分裂激酶组的磷酸化AURKA/B/C、AURKA、AURKB和PLK1显著增加。AURKA和AURKB蛋白的增加主要归因于转录后水平的调控，紫杉醇处理诱导Aurora激酶在AURKA（T288）/AURKB（T232）位点的蛋白磷酸化及其蛋白稳定性。在我们的UAB TNBC队列中，与相邻正常组织相比，TNBC肿瘤中AURKA和AURKB的表达显著更高，并且发现与欧裔美国人相比，非裔美国TNBC患者中AURKB高表达。此外，TNBC细胞中Aurora激酶的过表达使其对紫杉醇治疗产生抗性，并减弱化疗治疗引发的凋亡效应，表明Aurora激酶可介导TNBC中的化疗抗性。因此，Aurora激酶抑制剂或PROTAC降解剂与紫杉烷类化疗的联合使用显著增强了化疗效果。总之，我们揭示了化疗后Aurora激酶上调可赋予TNBC细胞化疗抗性，并且AURKB可作为分层患者对新辅助化疗反应的预选标志物。
