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Elevated Expression of Mitogen-Activated Protein Kinase Phosphatase 3 in Breast Tumors: A Mechanism of Tamoxifen Resistance

¹ Breast Center and ² Department of Medicine, Baylor College of Medicine, Houston, Texas; ³ Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan; ⁴ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana; and ⁵ Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff, United Kingdom

Requests for reprints: Suzanne A.W. Fuqua, Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: 713-798-1600; Fax: 713-798-1673; E-mail: sfuqua{at}breastcenter.tmc.edu.

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)

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