Aspirin Reduces Sensitivity Of Estrogen Receptor-positive Breast Cancer Cells To PI3K Inhibitors

The PI3K/Akt pathway is commonly over-activated in many tumor cells,such as estrogen receptor positive(ER+)mammary glands,where the frequency of PIK3CA gene mutations is as high as 40%.but the mechanism that PI3K/Akt abnormal activation leads to tumorigenesis is not well understood.FoxOs,negatively regulated by the PI3K/Akt pathway,are commonly thought to be tumor suppressors.The regulation of transcriptional activity of FoxO family members by acetylation modifications is much debated.Currently,tumors with PIK3CA mutations are usually treated clinically with PI3K inhibitors,but the therapeutic effect is not satisfactory and the mechanism of resistance is not clear.We identified the existence of protein-protein interactions between an epigenetic factor,FBPX,and FoxO3 through proteomic screening,and that FoxO3 acetylation status influences the interaction between the two.Aspirin treatment of cells induced FoxO3 acetylation while weakening the interaction of FoxO3 with FBPX.We further showed that in ER+breast cancer cells,FoxO3 and FBPX may regulate cellular sensitivity to PI3K inhibitors through the same pathway.The combination of 5 mM aspirin can reduce the sensitivity of cells to PI3K inhibitors when treated with low doses of PI3K inhibitors(GDC 0941,PI3Kα/β/γ/δ inhibitor at concentrations below 0.5 μM).FoxO3 downstream target genes,which were induced to be upregulated under PI3K inhibitor treatment conditions,were transcriptionally repressed under aspirin co-treatment conditions.Of note:knockdown of FBPX cells treated with PI3K inhibitors mimics the transcriptional repression of FoxO3 downstream target genes by aspirin.We hypothesized that aspirin-induced acetylation of FoxO3 may affect the transcriptional activity of FoxO3 by altering the protein profile that interacts with FoxO3(e.g.,downregulating the interaction of FoxO3 with FBPX).How FBPX,an epigenetic factor,regulates FoxO3-dependent gene transcription deserves further in-depth study.In summary,our study preliminarily explored the possible mechanisms by which aspirin reduces the susceptibility of ER+breast cancer cells to killing by PI3K inhibitors,and the specific mechanisms by which FoxO family molecules interact with the epigenetic factor FBPX in mediating drug sensitivity are the targets of our future research.