Mechanistic studies revealed that the overexpression and depletion of S1P1 in BC-derived cells increased and decreased the levels of both p-Smad2 and p-Smad3, respectively, and the levels of p-AKT, PTEN, P38, and p-ERK were not altered in BC-derived cells with ectopic S1P1 expression (Fig. 4b). This evidence concerns the gene SMAD2 and breast cancer.