The Role and Regulatory Mechanism of 14-3-3 Sigma in Human Breast Cancer.
10.4048/jbc.2014.17.3.207
- Author:
Seungsang KO
1
;
Ji Young KIM
;
Joon JEONG
;
Jong Eun LEE
;
Woo Ick YANG
;
Woo Hee JUNG
Author Information
1. Department of Surgery, Cheil General Hospital & Women's Health Care Center, Catholic Kwandong University College of Medicine, Seoul, Korea.
- Publication Type:Original Article
- Keywords:
Breast neoplasms;
Estrogen-responsive finger protein;
Methylation;
SFN protein
- MeSH:
Breast;
Breast Neoplasms*;
Cell Line;
Disease-Free Survival;
Down-Regulation;
Fingers;
Humans;
Immunohistochemistry;
Methylation;
Polymerase Chain Reaction;
Prognosis;
Proteolysis;
RNA, Small Interfering
- From:Journal of Breast Cancer
2014;17(3):207-218
- CountryRepublic of Korea
- Language:English
-
Abstract:
PURPOSE: 14-3-3 sigma (sigma) is considered to be an important tumor suppressor and decreased expression of the same has been reported in many malignant tumors by hypermethylation at its promoter or ubiquitin-mediated proteolysis by estrogen-responsive ring finger protein (Efp). In this study, we investigated the significance of 14-3-3 sigma expression in human breast cancer and its regulatory mechanism. METHODS: Efp was silenced using small interfering RNA (siRNA) in the MCF-7 breast cancer cell line in order to examine its influence on the level of 14-3-3 sigma protein. The methylation status of the 14-3-3 sigma promoter was also evaluated by methylation-specific polymerase chain reaction (PCR). The expression of Efp and 14-3-3 sigma in 220 human breast carcinoma tissues was assessed by immunohistochemistry. Other clinicopathological parameters were also evaluated. RESULTS: Silencing Efp in the MCF-7 breast cancer cell line resulted in increased expression of 14-3-3 sigma. The Efp-positive human breast cancers were more frequently 14-3-3 sigma-negative (60.5% vs. 39.5%). Hypermethylation of 14-3-3 sigma was common (64.9%) and had an inverse association with 14-3-3 sigma positivity (p=0.072). Positive 14-3-3 sigma expression was significantly correlated with poor prognosis: disease-free survival (p=0.008) and disease-specific survival (p=0.009). CONCLUSION: Our data suggests that in human breast cancer, the regulation of 14-3-3 sigma may involve two mechanisms: ubiquitin-mediated proteolysis by Efp and downregulation by hypermethylation. However, the inactivation of 14-3-3 sigma is probably achieved mainly by hypermethylation. Interestingly, 14-3-3 sigma turned out to be a very significant poor prognostic indicator, which is in contrast to its previously known function as a tumor suppressor, suggesting a different role of 14-3-3 sigma in breast cancer.
