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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2006-06, Vol.66 (11), p.5950-5959
• Main Authors: YUKUN CUI, PARRA, Irma, MAO ZHANG, HILSENBECK, Susan G, TSIMELZON, Anna, FURUKAWA, Toru, HORII, Akira, ZHANG, Zhong-Yin, NICHOLSON, Robert I, FUQUA, Suzanne A. W
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Drug Resistance, Neoplasm; Dual Specificity Phosphatase 6; Estrogen Receptor alpha - metabolism; Female; Gene Expression Profiling; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Protein Tyrosine Phosphatases - biosynthesis; Protein Tyrosine Phosphatases - genetics; Tamoxifen - pharmacology; Transcription, Genetic; Transfection; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-3243

Antiestrogen resistance is a major clinical problem in the treatment of breast cancer. Altered growth factor signaling with estrogen receptor (ER)-alpha 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-alpha-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 Ser(118)-ER-alpha, 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 NH(2)-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.