Abstract
The mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) belongs to the MAPK cascades which are central to cell proliferation and apoptosis. The carcinogenic role of MKP-1 has been reported in many types of cancer but it has rarely been investigated in breast cancer. The present study was designed to evaluate the MKP-1 mRNA expression and its possible regulation by methylation of MKP-1 promoter in the model of several breast cancer cell lines and tissues as well as controls. Our data demonstrate MKP-1 mRNA expression significantly decreased in five breast cancer cell lines compared to breast controls (P < 0.01). Using the methylation-specific PCR (MSP) analysis, the unmethylated reaction (U) is dominant in both normal cell lines and benign breast tumors (100% vs. 86.2%), whereas the methylated reaction (M) is dominant in both breast cancer cell lines and invasive breast tumors (100% vs. 57.2%). In terms of methylation ratio (M/M+U), methylation level in MKP-1 promoter is significantly higher in the invasive breast tumor tissues (n = 152) than in benign breast tumor tissues (n = 29) (P < 0.0001). Assessing the methylation ratio of the promoter of MKP-1 gene to diagnose the breast malignancy (invasive vs. benign), the area under the receiver-operating characteristic (ROC) curve was 0.809 (95% CI: 0.711-0.906, P < 0.001). The best performance for this prediction has a sensitivity of 76.32% and a specificity of 82.76% at the cutoff value of 0.38. Taken together, we firstly demonstrated that the promoter methylation of MKP-1 gene is a potential breast cancer biomarker for breast malignancy.
Highlights
Breast cancer remains a common malignancy among women
The tested breast cancer cell lines (MCF7, T47D, MDA-MB-231, SKBR3, and BT474) show the fold activation of 0.894 ± 0.003, 0.118 ± 0.008, 0.437 ± 0.020, 0.164 ± 0.014, 0.586 ± 0.026, respectively. It shows significantly reduction for mitogen-activated protein kinase phosphatase-1 (MKP-1) mRNA expressions in these five breast cancer cell lines compared to normal control (P < 0.01)
We focused on breast cancer and examined the mRNA expression of MKP-1 gene as well as its promoter methylation status
Summary
Breast cancer remains a common malignancy among women. The high incidence and prevalence of breast cancer represents a major public health problem and understanding the molecular features of breast cancer has been a central target in biomedical research. Some different types of cancers including prostate (Rauhala et al, 2005), liver (Loda et al, 1996), renal (Mizuno et al, 2004), and urothelial (Shimada et al, 2007) cancers showed decreased MKP-1 mRNA or protein expression. The MKP-1 mRNA in hormone-refractory prostate carcinomas was expressed at a lower level than in benign prostate hyperplasia or untreated prostate carcinomas (Rauhala et al, 2005). Most (80%) hepatocellular carcinomas expressed low levels of mRNA based on in situ hybridization analysis (Loda et al, 1996) In renal cancer, both Caki-1 and KU 20–01 cell lines showed decreased MKP-1 protein expression (Mizuno et al, 2004). The relative MKP-1 expression in breast cancer compared to normal
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