Pharmacological Reactivation of PP2A by SET/CIP2A Inhibition Attenuates Triple Negative Breast Cancer Progression

The tumor suppressor protein phosphatase 2A (PP2A) plays a crucial role in regulating oncogenic signaling. Its inactivation, specifically through inhibitory phosphorylation at Tyr307 mediated by SET and CIP2A, contributes to breast cancer (BC) progression. Modulation of these interactions represents a promising pharmacological strategy to restore PP2A function. We integrated computational approaches with experimental validation to analyse SET/CIP2A mechanisms and explore how PP2A reactivation suppresses tumor progression. Molecular docking and dynamics simulations showed that the SET inhibitor/FTY-720 forms stable hydrogen bond networks with SET, disrupting its interaction with PP2A. In contrast, CIP2A suppressor/erlotinib interacts with CIP2A through weaker hydrophobic and π-interactions. Protein–protein interaction analyses indicate reduced SET/CIP2A binding to PP2A upon treatment, supporting a structural basis for PP2A reactivation. Gene expression analyses revealed upregulation of PP2A, SET, CIP2A, and cytoskeletal markers in tumor and metastatic tissues. Studies on Triple Negative Breast Cancer (TNBC) cells showed that FTY-720 and erlotinib significantly reduce PP2A-Tyr307 phosphorylation, restoring its activity. Additionally, both compounds decreased c-Myc levels and inhibited Src/FAK/paxillin/PAK1 and ERK signaling, attenuating migratory and proliferative pathways. Our findings identify the SET/CIP2A–PP2A axis as a pharmacological target for the design of next-generation PP2A activators, highlighting the potential of inhibition as a therapeutic strategy to counteract TNBC progression.