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Published on: May 17, 2019
Decreased total MKP-1 protein levels predict poor prognosis in breast cancer
Ming-Feng Hou1, Chien-Wei Chang, Fang-Ming Chen
1Department of Surgery, Cancer Center and Division of General & Gastroenterological Surgery, Kaohsiung Medical University Hospital, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung City, 807, Taiwan, ROC. mifeho@kmu.edu.tw
Background:
MKP-1 dephosphorylates and inactivates MAPKs, whose constitutive activations have been associated with human cancers.
Results:
We found that total MKP-1 protein levels were decreased in 63.7 % of breast cancer tissues compared with the paired noncancerous breast tissues. Decreased MKP-1 protein levels were correlated with increased tumor stage and positive recurrence and were associated with poor survival, even when using a multivariate Cox regression model. Intriguingly, nuclear MKP-1 staining was positively correlated with ER status. In vitro, tamoxifen increased MKP-1 expression in ER-positive but not ER-negative breast cancer cells. ER-specific siRNA was able to attenuate tamoxifen-induced MKP-1 expression. Furthermore, tamoxifen prolonged the duration of MKP-1 elevation and the binding time of ER to the promoter of the MKP-1/DUSP-1 gene compared with estrogen.
Conclusions:
Our results suggest that alterations of MKP-1 may serve as a prognostic factor in breast cancer. In addition, the regulation of MKP-1 may be related to the ER.
Insights
Decreased levels of MKP-1 (mitogen-activated protein kinase phosphatase-1) protein are linked to poorer breast cancer prognosis. Estrogen receptor status influences MKP-1 regulation by tamoxifen.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Mitogen-activated protein kinase phosphatase-1 (MKP-1) dephosphorylates and inactivates MAPKs.
- Constitutive activation of MAPKs is implicated in human cancers.
Purpose of the Study:
- To investigate the role of MKP-1 in breast cancer.
- To explore the relationship between MKP-1, tumor characteristics, and patient survival.
- To examine the influence of estrogen receptor (ER) status on MKP-1 regulation.
Main Methods:
- Analysis of MKP-1 protein levels in breast cancer tissues versus paired noncancerous tissues.
- Correlation analysis between MKP-1 levels, tumor stage, recurrence, and survival using multivariate Cox regression.
- In vitro studies using ER-positive and ER-negative breast cancer cell lines treated with tamoxifen and ER-specific siRNA.
- Assessment of ER binding to the MKP-1/DUSP-1 gene promoter.
Main Results:
- Reduced MKP-1 protein levels were observed in 63.7% of breast cancer tissues.
- Lower MKP-1 levels correlated with advanced tumor stage, positive recurrence, and poorer survival.
- Nuclear MKP-1 staining positively correlated with ER status.
- Tamoxifen increased MKP-1 expression in ER-positive cells, an effect attenuated by ER-specific siRNA.
- Tamoxifen prolonged MKP-1 elevation and ER binding to the MKP-1/DUSP-1 promoter compared to estrogen.
Conclusions:
- MKP-1 alterations may serve as a prognostic factor in breast cancer.
- MKP-1 regulation in breast cancer is potentially linked to the estrogen receptor.