The Role of CHK1 Varies with the Status of Oestrogen-receptor and Progesterone-receptor in the Targeted Therapy for Breast Cancer
The Role of CHK1 Varies with the Status of Oestrogen-receptor and Progesterone-receptor in the Targeted Therapy for Breast Cancer
复制标题
CHK1在乳腺癌靶向治疗中的作用随雌激素受体和孕激素受体的状态而变化
DOI：
10.7150/ijbs.41627
复制
发表时间：
2020-01-01
影响因子：
9.2
通讯作者：
Mu, Kun
中科院分区：
文献类型：
--
作者：
Xu, Wei;Huang, Minghua;Mu, Kun
目的：针对检查点激酶1（checkpoint kinase 1，CHK 1）的靶向抑制在肿瘤治疗中的疗效已得到证实，但如何在具有异质性分子特征的乳腺癌中选择有效的应用方法仍不清楚。通过药物敏感性试验、细胞增殖试验、细胞周期和凋亡分析检测CHK 1抑制剂对不同ER/PR状态乳腺癌的化疗敏感性和单药抗肿瘤活性。结果：在ER-/PR-/HER 2（-）乳腺癌中，CHK 1抑制可增强阿霉素（ADR）化疗敏感性，这一作用通过有丝分裂检查点复合物（MCC）-后期促进复合物/细胞周期小体（APC/C）-细胞周期蛋白B1轴、Msh同源框2（MSX 2）和Bcl-2样蛋白11（BIM）介导。然而，在ER+/PR+/HER 2（-）乳腺癌中，由于ADR本身诱导的着丝粒蛋白F（CENPF）介导的CHK 1转录激活受到显著抑制，CHK 1抑制未能使ADR毒性敏感。CHK 1抑制剂在ER+/PR+/HER 2（-）乳腺癌中表现出单一药物的抗肿瘤活性，其作用是由细胞周期蛋白依赖性激酶抑制剂1A（p21）、驱动蛋白家族成员11（Eg 5）和细胞表面死亡受体（Fas）介导的。
Objective: The therapeutic effects of the checkpoint kinase 1 (CHK1)-targeted inhibition in tumor therapy have been confirmed, but how to choose an effective application method in breast cancer with heterogeneous molecular characteristics has remained unclear.Methods: We evaluated the status of CHK1 in breast cancer using the cancer genome atlas database. Chemosensitivity and single-agent antitumor activity of CHK1 inhibition were measured by drug sensitivity assay, cell proliferation assay, cell cycle and apoptosis analysis in breast cancer with different ER/PR status. And based on the conjoint transcriptome atlas analyses, the corresponding mechanism were explored.Results: In ER-/PR-/HER2(-) breast cancer, CHK1 inhibition enhanced adriamycin (ADR) chemosensitivity which was mediated by the mitotic checkpoint complex (MCC)-anaphase-promoting complex/cyclosome (APC/C)-cyclin B1 axis, Msh homeobox 2 (MSX2) and Bcl-2-like protein 11 (BIM). However, in ER+/PR+/HER2(-) breast cancer, because of the significant suppression for centromere protein F (CENPF)-mediated transcriptional activation of CHK1 induced by ADR itself, CHK1 inhibition fails to sensitize ADR toxicity. Interestingly, CHK1 inhibition showed the single-agent antitumor activity in ER+/PR+/HER2(-) breast cancer which was mediated by the cyclin dependent kinase inhibitor 1A (p21), kinesin family member 11 (Eg5) and cell surface death receptor (Fas).Conclusions: CHK1's variable role determines the application of CHK1 inhibition in breast cancer with ER/PR heterogeneity.