The role of CHK1 varies with the status of oestrogen-receptor and progesterone-receptor in the targeted therapy for breast cancer

Abstract

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.