Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: a mechanism of tamoxifen resistance.
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.
Cui
Yukun
Y
Breast Center and Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
Parra
Irma
I
Zhang
Mao
M
Hilsenbeck
Susan G
SG
Tsimelzon
Anna
A
Furukawa
Toru
T
Horii
Akira
A
Zhang
Zhong-Yin
ZY
Nicholson
Robert I
RI
Fuqua
Suzanne A W
SA
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D054642:Dual Specificity Phosphatase 6; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis* / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*; D014158:Transcription, Genetic; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D020928:Mitogen-Activated Protein Kinases; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse; D017027:Protein Tyrosine Phosphatases