Breast cancer presents significant challenges due to its aggressive nature and the limited efficacy of current treatments. Our study focuses on PP2A, a key regulator in tumorigenesis. Phosphorylation at Tyr307 by CIP2A and SET critically inhibits the tumor suppressor function of PP2A and promotes metastasis. Therefore, our research aims to restore PP2A activity by targeting CIP2A and SET. First, we investigated the expression of PP2A, including its phosphorylated form (p-PP2A), in various breast cancer cell subtypes. Through extensive computational and experimental analysis, we identified high levels of p-PP2A in a triple-negative breast cancer cell line. In molecular docking and dynamics studies, Erlotinib interacts primarily hydrophobically with CIP2A, while FTY-720 binds to SET via hydrogen bonding and hydrophobic forces, stabilizing protein-drug complexes. Protein-protein docking simulations indicated that these drugs reduce the specific phosphorylation of PP2ATyr307 by CIP2A and SET, suggesting an indirect regulatory mechanism. In vitro experiments demonstrated the potent inhibitory effects of erlotinib and FTY-720 on CIP2A and SET, preventing PP2A/Tyr307 phosphorylation and restoring tumor suppressive function. In addition, these drugs disrupted key processes of cell migration and invasion, thereby counteracting metastasis. Our hypothesis proposes that targeting CIP2A and SET with Erlotinib and FTY-720 could effectively attenuate breast cancer metastasis by restoring PP2A activity. In conclusion, our research highlights the potential of Erlotinib and FTY-720 as promising therapeutic agents for breast cancer, particularly TNBC, by modulating PP2A regulatory pathways to suppress metastasis. Further clinical validation is critical to substantiate their therapeutic efficacy