Abstract
BackgroundTamoxifen 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.MethodsWe first tested whether peptidylarginine deiminase 2 (PAD2) may be involved in tamoxifen-resistance in breast cancer cells. The effect of depleting or inhibiting PAD2 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 PAD inhibitor, to be used in combination with tamoxifen or docetaxel, and further explored the mechanism of the synergistic and effective drug regimen of PADs inhibitor and docetaxel on tamoxifen-resistant breast cancer cells.ResultsWe report that PAD2 is dramatically upregulated in tamoxifen-resistant breast cancer. Depletion of PAD2 in MCF7/TamR cells facilitated the sensitivity of MCF7/TamR cells to tamoxifen. Moreover, miRNA-125b-5p negatively regulated PAD2 expression in MCF7/TamR cells, therefore overexpression of miR-125b-5p also increased the cell sensitivity to tamoxifen. Furthermore, inhibiting PAD2 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.ConclusionOur results suggest that PAD2 functions as an important new biomarker for tamoxifen-resistant breast cancers and that inhibiting PAD2 combined with docetaxel may offer a new approach to treatment of tamoxifen-resistant breast cancers.
Highlights
Tamoxifen resistance presents a huge clinical challenge for breast cancer patients
peptidylarginine deiminase 2 (PAD2) expression is highly upregulated in tamoxifenresistant breast cancer, and depletion of PAD2 facilitates the sensitivity of MCF7/TamR cells to tamoxifen To determine the clinical significance of PAD2 in tamoxifen-resistant breast tumors, we first examined PAD2 mRNA level in clinical tumor tissue microarray during tamoxifen therapy using the publicly GEO dataset GDS806/11785 [24]
PAD2 transcript was more highly expressed in MCF7/ TamS cells compared to the other Peptidylarginine deiminases (PADs) family members (Fig. 1c), and only PAD2 was significantly upregulated in TamR/MCF7 cell (Fig. 1c and d)
Summary
Tamoxifen resistance presents a huge clinical challenge for breast cancer patients. As one of the most prescribed ER antagonists for first line adjuvant endocrine therapy, has significant efficacy for ER-positive breast cancer, and has been shown to substantially reduce recurrence and mortality rate in ER-positive breast cancer patients [2]. Docetaxel is still the first-line chemotherapy in breast cancer and constitutes one of the most effective classes of chemotherapeutics for prolonged survival in advanced disease [8, 9]. It is of high clinical significance to enhance the efficacy of docetaxel using lower doses in a less toxic manner and to reduce its side effects. Therapeutic strategies that can either increase the effects of chemotherapeutics or decrease the dosage are urgently needed for the treatment of tamoxifen-resistant breast cancers
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