Characterizing The Molecular Mechanisms Underlying FoxO4-dependent Regulation Of Sensitivity To PI3K Inhibitors In ER Positive Breast Cancer

Estrogen receptor-positive(ER+)breast cancer is the most common subtype of breast cancer.Many papers have reported that the PI3K signaling pathway plays an important role in the development of tumors,especially in breast cancer.The frequency of mutations in the class I phosphatidylinositol-3-kinase(PI3K)family of molecules reaches nearly 60%in ER+(estrogen receptor-positive)breast cancers,while the frequency of activating mutations in the PIK3CA gene(encoding the p110 catalytic subunit of PI3K,p110α),can reach 40%in estrogen receptor(ER+)positive breast cancers.As a result,PI3Ki(PI3K inhibitor)has good clinical promise for the treatment of ER-positive breast cancer with PIK3CA mutation,and there are two main inhibitors that are now widely used,BYL-719(mainly inhibits p110α)and GDC-0941(inhibits PI3Kα/β/γ/δ).In fact,PI3K inhibitors have shown clear antitumor efficacy in preclinical trials,but in recent years many research groups have successively reported the phenotype of PI3Ki resistance in tumor cells,and the mechanisms of resistance include gene mutations,epigenetic changes and changes in the tumor microenvironment,but this is only the tip of the iceberg of research on PI3Ki resistance.However,it is still unclear whether FOXO family molecules activated by PI3Ki are involved in the process of inducing cellular drug resistance.Our study focuses on resolving whether FOXO is involved in the induction of PI3Ki drug resistance and its molecular mechanism,as well as finding targets.Our data suggest that JMJD3 plays a key role in regulating the transcription of FOXO4 transcription factors and that the synergistic transcriptional regulation of FOXO4 and JMJD3 may be one of the mechanisms that induce PI3Ki resistance.F4BX may be the upstream transcription factor that directly regulates FOXO4 under PI3Ki treatment conditions.The results suggest that FOXO4 and JMJD3 may serve as targets for combined PI3Ki synergistic treatment of ER+breast cancer.Our results illustrate the possible mechanism by which FOXO4 undergoes transcriptional upregulation under PI3Ki treatment and the possible mechanism by which FOXO4 interacts with JMJD3 to regulate PI3K resistance,the specific mechanism of which still needs our continued investigation.