The Role of CHK1 Varies with the Status of Oestrogen-receptor and Progesterone-receptor in the Targeted Therapy for Breast Cancer
Wei Xu, Minghua Huang, Jia Guo, Huiting Zhang, Depeng Wang, Tiantian Liu, Haiting Liu, Shiming Chen, Peng Gao, Kun Mu
Abstract
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.