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

Abstract

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.

• Authors: Yukun Cui, Irma Parra, Mao Zhang, Susan G Hilsenbeck, Anna Tsimelzon, Toru Furukawa, Akira Horii, Zhong-Yin Zhang, Robert I Nicholson, Suzanne A W Fuqua
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 11 Pg. 5950-9 (Jun 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16740736 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Estrogen Receptor alpha
• Tamoxifen
• Mitogen-Activated Protein Kinases
• DUSP6 protein, human
• Dual Specificity Phosphatase 6
• Dusp6 protein, mouse
• Protein Tyrosine Phosphatases

Topics

• Animals
• Breast Neoplasms (drug therapy, enzymology, genetics)
• Drug Resistance, Neoplasm
• Dual Specificity Phosphatase 6
• Estrogen Receptor alpha (metabolism)
• Female
• Gene Expression Profiling
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitogen-Activated Protein Kinases (metabolism)
• Protein Tyrosine Phosphatases (biosynthesis, genetics)
• Tamoxifen (pharmacology)
• Transcription, Genetic
• Transfection
• Xenograft Model Antitumor Assays