BAG2 drives chemoresistance of breast cancer by exacerbating mutant p53 aggregate.
BAG2 drives chemoresistance of breast cancer by exacerbating mutant p53 aggregate.
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BAG2通过加剧突变p53聚集来驱动乳腺癌的化疗耐药性
DOI：
10.7150/thno.78492
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发表时间：
2023
期刊：
影响因子：
12.4
通讯作者：
Lin, Chuyong
中科院分区：
文献类型：
--
作者：
Huang, Xinjian;Shi, Dongni;Zou, Xuxiazi;Wu, Xuxia;Huang, Shumei;Kong, Lingzhi;Yang, Muwen;Xiao, Yunyun;Chen, Boyu;Chen, Xiangfu;Ouyang, Ying;Song, Libing;Jian, Yunting;Lin, Chuyong
理由：化疗耐药性是乳腺癌患者临床管理的主要挑战。突变型p53蛋白倾向于形成促进癌症中肿瘤发生的聚集体。本研究旨在探讨乳腺癌中突变型p53聚集体的产生机制，并评估其在诱导化疗耐药中的作用。研究方法：通过qRT-PCR、蛋白质印迹和免疫组织化学评价乳腺癌患者标本中BCL 2相关的嗜酸性基因2（BAG 2）的表达。采用Kaplan-Meier生存分析和考克斯回归模型评估BAG 2表达对预后的意义。通过免疫共沉淀、免疫荧光和半变性洗涤剂琼脂糖凝胶电泳分析BAG 2在促进突变型p53聚集体形成中的作用。通过细胞功能测定和小鼠肿瘤模型证实了BAG 2对乳腺癌化疗耐药性的影响。结果如下：在本研究中，我们发现BAG 2在复发性乳腺癌患者组织中显著上调，并且高BAG 2与更差的预后相关。BAG 2定位于突变型p53聚集体中并与错误折叠的p53突变体相互作用。BAG 2促进聚集体的形成，并募集HSP 90以促进聚集体的增殖和维持。因此，BAG 2介导的突变型p53聚集抑制线粒体凋亡途径，导致乳腺癌的化疗耐药。重要的是，BAG 2的沉默或HSP 90的药理学靶向大大减少了聚集体，并增加了乳腺癌化疗的敏感性。结论：这些发现揭示了BAG 2通过加剧突变型p53聚集体在乳腺癌化疗耐药性中的重要作用，并表明BAG 2可作为耐药乳腺癌患者的潜在治疗靶点。
Rationale: Chemoresistance is a major challenge in the clinical management of patients with breast cancer. Mutant p53 proteins tend to form aggregates that promote tumorigenesis in cancers. We here aimed to explore the mechanism for the generation of mutant p53 aggregates in breast cancer and assess its role in inducing chemoresistance. Methods: Expression of BCL2-associated athanogene 2 (BAG2) was evaluated by qRT-PCR, western blotting, and immunohistochemistry in breast cancer patient specimens. The significance of BAG2 expression in prognosis was assessed by Kaplan-Meier survival analysis and the Cox regression model. The roles of BAG2 in facilitating the formation of mutant p53 aggregates were analyzed by co-immunoprecipitation, immunofluorescence, and semi-denaturing detergent-agarose gel electrophoresis assays. The effects of BAG2 on the chemoresistance of breast cancer were demonstrated by cell function assays and mice tumor models. Results: In the present study, we found that BAG2 was significantly upregulated in relapse breast cancer patient tissues and high BAG2 was associated with a worse prognosis. BAG2 localized in mutant p53 aggregates and interacted with misfolded p53 mutants. BAG2 exacerbated the formation of the aggregates and recruited HSP90 to promote the propagation and maintenance of the aggregates. Consequently, BAG2-mediated mutant p53 aggregation inhibited the mitochondrial apoptosis pathway, leading to chemoresistance in breast cancer. Importantly, silencing of BAG2 or pharmacological targeting of HSP90 substantially reduced the aggregates and increased the sensitivity of chemotherapy in breast cancer. Conclusion: These findings reveal a significant role of BAG2 in the chemoresistance of breast cancer via exacerbating mutant p53 aggregates and suggest that BAG2 may serve as a potential therapeutic target for breast cancer patients with drug resistance.
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