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Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: A mechanism of Tamoxifen resistance

Cui, Yukin, Parra, Irma, Zhang, Mao, Hilsenbeck, Susan G., Tsimelzon, Anna, Furukawa, Toru, Horii, Akira, Zhang, Zhong-Yin, Nicholson, Robert Ian and Fuqua, Suzanne 2006. Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: A mechanism of Tamoxifen resistance. Cancer Research 66 (11) , pp. 5950-5959. 10.1158/0008-5472.CAN-05-3243

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Abstract

Antiestrogen resistance is a major clinical problem in the treatment of breast cancer. Altered growth factor signaling with estrogen receptor (ER)-? is associated with the development of resistance. Gene expression profiling was used to identify mitogen-activated protein kinase (MAPK) phosphatase 3 (MKP3) whose expression was correlated with response to the antiestrogen tamoxifen in both patients and in vitro–derived cell line models. Overexpression of MKP3 rendered ER-?-positive breast cancer cells resistant to the growth-inhibitory effects of tamoxifen and enhanced tamoxifen agonist activity in endometrial cells. MKP3 overexpression was associated with lower levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in the presence of estrogen but that estrogen deprivation and tamoxifen treatment decreased MKP3 phosphatase activity, leading to an up-regulation of pERK1/2 MAPK, phosphorylated Ser118-ER-?, and cyclin D1. The MAPK/ERK kinase inhibitor PD98059 blocked tamoxifen-resistant growth. Accumulation of reactive oxygen species was observed with tamoxifen treatment of MKP3-overexpressing cells, and antioxidant treatment increased MKP3 phosphatase activity, thereby blocking resistance. Furthermore, PD98059 increased the levels of phosphorylated c-Jun NH2-terminal kinase (JNK) in tamoxifen-treated MKP3-overexpressing cells, suggesting an interaction between MKP3 levels, activation of ERK1/2 MAPK, and JNK signaling in human breast cancer cells. MKP3 represents a novel mechanism of resistance, which may be a potential biomarker for the use of ERK1/2 and/or JNK inhibitors in combination with tamoxifen treatment. (Cancer Res 2006; 66(11): 5950-9)

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
ISSN: 15387445
Last Modified: 19 Mar 2016 22:02
URI: http://orca-mwe.cf.ac.uk/id/eprint/939

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