Mitogen-activated protein kinase phosphatase 1 is involved in tamoxifen resistance in MCF7 cells.
Tamoxifen resistance is a major clinical problem for ER-positive breast cancer, but the underlying mechanism is not completely elucidated. In the present study, we reported that mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1), a member of the family of MKPs, is involved in tamoxifen resistance. We found that MKP1 expression increased in tamoxifen resistant MCF7 cells. To explore the possible role of MKP1 in tamoxifen resistance, siRNA targeting MKP1 was transfected into tamoxifen resistant MCF7 cells. To our surprise, knockdown of MKP-1 promoted cell death induced by tamoxifen. On the other hand, the MKP1 overexpressed MCF7 cell clone was established and MKP1 overexpression effectively attenuated MCF7 cell death induced by tamoxifen. In addition, we revealed that MKP1 inhibited tamoxifen‑mediated JNK activation in tamoxifen resistant MCF7 and MCF7 cells, and by this mechanism MKP1 was able to inhibit tamoxifen-induced cell death. We also showed that combined appliaction of MKP1 inhibitor triptolide and tamoxifen can effectively increase tamoxifen sensitivity in tamoxifen resistant MCF7 cells. Collectively, our results indicated that MKP-1 can attenuate tamoxifen-induced cell death through inhibiting the JNK signal pathway, which represents a novel mechanism of tamoxifen resistance in MCF7 cells.
Department of Breast Surgery, The First Affiliated Hospital, Medicine College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Gang
G
Ma
Department of Gynecology, Northwest Women and Childrens Hospital, Xi'an, Shaanxi 710061, P.R. China.
Yixia
Y
Pan
Department of Breast Surgery, The First Affiliated Hospital, Medicine College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Can
C
Zhou
Department of Pathology, Medicine College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Ruifang
R
Sun
Shaanxi Province People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
Jingjing
J
Bai
Department of Translational Medicine Center, The First Affiliated Hospital, Medicine College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Peijun
P
Liu
Department of Breast Surgery, The First Affiliated Hospital, Medicine College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Yu
Y
Ren
Department of Breast Surgery, The First Affiliated Hospital, Medicine College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Jianjun
J
He
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis; D019008:Drug Resistance, Neoplasm; D054638:Dual Specificity Phosphatase 1; D006801:Humans; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D015854:Up-Regulation
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D020928:Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1