The phosphorylated prodrug FTY720 is a histone deacetylase Q15 inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer

Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate (S1P) receptors. We found that FTY720 is phosphorylated in Era-negative breast cancer cells by nuclear sphingosine kinase 2 and accumulates these cells. To determine whether FTY720-P inhibits HDACs in Era-negative breast cancer cells and in tumors to regulate histone acetylation and gene expression, and it can re-express ERα in these aggressive breast carcinoma for hormonal therapies.