Inhibiting PAD2 enhances the anti-tumor effect of docetaxel in tamoxifen-resistant breast cancer cells.

BACKGROUND:Tamoxifen resistance presents a huge clinical challenge for breast cancer patients. An understanding of the mechanisms of tamoxifen resistance can guide development of efficient therapies to prevent drug resistance. METHODS:We first tested whether peptidylarginine deiminase 2 may be involved in tamoxifen-resistance in breast cancer cells. The effect of depleting or inhibiting in tamoxifen-resistant MCF-7 (MCF7/TamR) cells was evaluated both in vitro and in vivo. We then investigated the potential of Cl-amidine, a inhibitor, to be used in combination with tamoxifen or docetaxel, and further explored the mechanism of the synergistic and effective drug regimen of inhibitor and docetaxel on tamoxifen-resistant breast cancer cells. RESULTS:We report that duanyu15632 is dramatically upregulated in tamoxifen-resistant breast cancer. Depletion of duanyu15632 in MCF7/TamR cells facilitated the sensitivity of MCF7/TamR cells to tamoxifen. Moreover, miRNA-125b-5p negatively regulated duanyu15632 expression in MCF7/TamR cells, therefore overexpression of miR-125b-5p also increased the cell sensitivity to tamoxifen. Furthermore, inhibiting duanyu15632 with Cl-amidine not only partially restored the sensitivity of MCF7/TamR cells to tamoxifen, but also more efficiently enhanced the efficacy of docetaxel on MCF7/TamR cells with lower doses of Cl-amidine and docetaxel both in vivo and in vivo. We then showed that combination treatment with Cl-amidine and docetaxel enhanced p53 nuclear accumulation, which synergistically induced cell cycle arrest and apoptosis. Meanwhile, p53 activation in the combination treatment also accelerated autophagy processes by synergistically decreasing the activation of Akt/mTOR signaling, thus enhancing the inhibition of proliferation. CONCLUSION:Our results suggest that duanyu15632 functions as an important new biomarker for tamoxifen-resistant breast cancers and that inhibiting duanyu15632 combined with docetaxel may offer a new approach to treatment of tamoxifen-resistant breast cancers.

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