Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Department of Clinical Oncology, Queen Mary Hospital, Hong Kong SAR, China.
Int J Mol Sci. 2022 Oct 14;23(20):12290. doi: 10.3390/ijms232012290.
Breast cancer is a heterogeneous disease. Tamoxifen is frequently used to treat ER-positive breast cancer. Our team has identified a novel splice variant of NCOR2, BQ323636.1 (BQ), that mediates tamoxifen resistance. However, the upstream factors that modulate BQ expression are not apparent. This study reveals that tamoxifen treatment causes induction of DNA damage which can enhance BQ expression. We show that DNA damage can activate the ATM/CHK2 and ATR/CHK1 signalling cascades and confirm that ATM/CHK2 signalling is responsible for enhancing the protein stability of BQ. siRNA or a small inhibitor targeting CHK2 resulted in the reduction in BQ expression through reduced phosphorylation and enhanced poly-ubiquitination of BQ. Inhibition of CHK2 by CCT241533 could reverse tamoxifen resistance in vitro and in vivo. Using clinical samples in the tissue microarray, we confirmed that high p-CHK2 expression was significantly associated with high nuclear BQ expression, tamoxifen resistance and poorer overall and disease-specific survival. In conclusion, tamoxifen treatment can enhance BQ expression in ER-positive breast cancer by activating the ATM/CHK2 axis. Targeting CHK2 is a promising approach to overcoming tamoxifen resistance in ER-positive breast cancer.
乳腺癌是一种异质性疾病。他莫昔芬常用于治疗 ER 阳性乳腺癌。我们的团队已经鉴定出 NCOR2 的一种新型剪接变体 BQ323636.1（BQ），它介导他莫昔芬耐药。然而，调节 BQ 表达的上游因素尚不清楚。本研究表明，他莫昔芬治疗会引起 DNA 损伤的诱导，从而增强 BQ 的表达。我们表明，DNA 损伤可以激活 ATM/CHK2 和 ATR/CHK1 信号级联，并证实 ATM/CHK2 信号负责增强 BQ 的蛋白稳定性。siRNA 或针对 CHK2 的小抑制剂通过减少 BQ 的磷酸化和增强多泛素化导致 BQ 表达减少。CCT241533 抑制 CHK2 可在体外和体内逆转他莫昔芬耐药。使用组织微阵列中的临床样本，我们证实高 p-CHK2 表达与核 BQ 表达高、他莫昔芬耐药以及总体和疾病特异性生存率差显著相关。总之，他莫昔芬治疗通过激活 ATM/CHK2 轴可以增强 ER 阳性乳腺癌中的 BQ 表达。靶向 CHK2 是克服 ER 阳性乳腺癌他莫昔芬耐药的一种很有前途的方法。
