Functions And Mechanisms Of The Interaction Between FoxO1 And METTL3 In The Anti-tumor Effect Of PARP Inhibitors

Triple-negative breast cancer(TNBC)is a subtype of breast cancer that accounts for 10%to 19%of all breast cancers.The prognosis of TNBC is poor because the cell surface-specific antigens HER2,ER and PR are not expressed,making targeted therapy impossible.Studies have shown that most of the breast cancer susceptibility genes are related to DNA damage responses,especially DNA damage repair pathways,which makes TNBC more susceptible to drugs that target DNA damage responses.It is generally accepted that BRCA1 and BRCA2 are the most pivotal suppressor genes in breast cancer,and nearly 50%of TNBC formation is caused by homologous recombination defects caused by BRCA1/2 mutations.The ability of polyadenosine diphosphate ribose polymerase inhibitors(PARPi)to block the base excision repair(BER)pathway has been documented.Especially for BRCA1/2 mutated tumors,PARPi’s "synthetic lethal" effect can induce massive cell death.Clinically,PARPi has shown good antitumor efficacy in BRCA1/2 mutated TNBC.However,studies have shown that BRCA1/2-unmutated cancer cells are nearly 1,000-fold less sensitive to PARPi than BRCA1/2-mutated tumor cells.How to make PARPi effectively kill tumors with normal homologous recombination repair has become a difficult and hot topic in TNBC therapy.The transcription factor FoxO1 and the methyltransferase METTL3 regulate a variety of biological processes,which are closely related to tumor formation.We used BRCA1/2 wild-type TNBC cells as the subject of our study and found that FoxO1 and METTL3 are involved in DNA damage repair in TNBC cells.Our data illustrate that FoxO1 has a direct interaction with METTL3 and that METTL3 is important in regulating the binding of FoxO1 transcription factor to DNA.FoxO1 and METTL3 transcriptionally regulate DNA damage-repair-related genes,thereby altering the level of DNA damage in TNBC cells and affecting cellular sensitivity to PARPi.Our study initially suggests that the synergistic transcriptional regulation of FoxO1 and METTL3 may be one of the mechanisms affecting PARPi sensitivity,and both may become new molecular targets for combined PARPi synergistic treatment of TNBC.The specific mechanism remains to be further investigated.