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

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

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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)-α 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-α-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-α, 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.

Original languageEnglish
Pages (from-to)5950-5959
Number of pages10
JournalCancer Research
Volume66
Issue number11
DOIs
StatePublished - Jun 1 2006

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Dual Specificity Phosphatase 6
Dual Specificity Phosphatase 1
Tamoxifen
Breast Neoplasms
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
JNK Mitogen-Activated Protein Kinases
Estrogen Receptors
Estrogen Receptor Modulators
Phosphoric Monoester Hydrolases
Estrogens
Therapeutics
Cyclin D1
Mitogen-Activated Protein Kinase Kinases
Gene Expression Profiling
Growth
Mitogen-Activated Protein Kinases
Cell Communication
Reactive Oxygen Species
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cui, Y., Parra, I., Zhang, M., Hilsenbeck, S. G., Tsimelzon, A., Furukawa, T., ... Fuqua, S. A. W. (2006). Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: A mechanism of tamoxifen resistance. Cancer Research, 66(11), 5950-5959. https://doi.org/10.1158/0008-5472.CAN-05-3243

Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors : A mechanism of tamoxifen resistance. / Cui, Yukun; Parra, Irma; Zhang, Mao; Hilsenbeck, Susan G.; Tsimelzon, Anna; Furukawa, Toru; Horii, Akira; Zhang, Zhong-Yin; Nicholson, Robert I.; Fuqua, Suzanne A W.

In: Cancer Research, Vol. 66, No. 11, 01.06.2006, p. 5950-5959.

Research output: Contribution to journalArticle

Cui, Y, Parra, I, Zhang, M, Hilsenbeck, SG, Tsimelzon, A, Furukawa, T, Horii, A, Zhang, Z-Y, Nicholson, RI & Fuqua, SAW 2006, 'Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: A mechanism of tamoxifen resistance', Cancer Research, vol. 66, no. 11, pp. 5950-5959. https://doi.org/10.1158/0008-5472.CAN-05-3243
Cui, Yukun ; Parra, Irma ; Zhang, Mao ; Hilsenbeck, Susan G. ; Tsimelzon, Anna ; Furukawa, Toru ; Horii, Akira ; Zhang, Zhong-Yin ; Nicholson, Robert I. ; Fuqua, Suzanne A W. / Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors : A mechanism of tamoxifen resistance. In: Cancer Research. 2006 ; Vol. 66, No. 11. pp. 5950-5959.
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