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15-Deoxi-Δ12,14-prostaglandin J2 (15d-PGJ2) is known to play an important role in the pathophysiology of carcinogenesis, however, the molecular mechanisms underlying these effects are not yet fully understood. Recently, we have shown that 15d-PGJ2 is a potent inducer of breast cancer cell death and that this effect is associated with a disruption of the microtubule cytoskeletal network. Here, we show that treatment of the MCF-7 breast cancer cell line with 15d-PGJ2 induces an accumulation of cells in the G2/M compartment of the cell cycle and a marked disruption of the microtubule network. 15d-PGJ2 treatment causes mitotic abnormalities that consist of failure to form a stable metaphase plate, incapacity to progress through anaphase, and failure to complete cytokinesis. 15d-PGJ2 binds to tubulin through the formation of a covalent adduct with at least four cysteine residues in α- and β-tubulin, as detected by hybrid triple-quadrupole mass spectrometry analysis. Overall, these results support the hypothesis that microtubule disruption and mitotic arrest, as a consequence of the binding of 15d-PGJ2 to tubulin, can represent one important pathway leading to breast cancer cell death.