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The role and regulatory mechanism of 14-3-3 sigma in human breast cancer.

Ko S, Kim JY, Jeong J, Lee JE, Yang WI, Jung WH - J Breast Cancer (2014)

Bottom Line: 14-3-3 sigma (σ) 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).Positive 14-3-3 σ expression was significantly correlated with poor prognosis: disease-free survival (p=0.008) and disease-specific survival (p=0.009).However, the inactivation of 14-3-3 σ is probably achieved mainly by hypermethylation.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Cheil General Hospital & Women's Health Care Center, Catholic Kwandong University College of Medicine, Seoul, Korea.

ABSTRACT

Purpose: 14-3-3 sigma (σ) 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 σ 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 σ protein. The methylation status of the 14-3-3 σ promoter was also evaluated by methylation-specific polymerase chain reaction (PCR). The expression of Efp and 14-3-3 σ 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 σ. The Efp-positive human breast cancers were more frequently 14-3-3 σ-negative (60.5% vs. 39.5%). Hypermethylation of 14-3-3 σ was common (64.9%) and had an inverse association with 14-3-3 σ positivity (p=0.072). Positive 14-3-3 σ 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 σ may involve two mechanisms: ubiquitin-mediated proteolysis by Efp and downregulation by hypermethylation. However, the inactivation of 14-3-3 σ is probably achieved mainly by hypermethylation. Interestingly, 14-3-3 σ 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 σ in breast cancer.

No MeSH data available.


Related in: MedlinePlus

Disease-free survival and disease-specific survival curves according to 14-3-3 σ expression in each subgroup. (A, C, E) Disease-free survival; (B, D, F) Disease-specific survival. (A, B) Total cases: 14-3-3 σ expression was significantly associated with an increased risk of recurrence and disease-related death. (C, D) Receptor-positive group: 14-3-3 σ expression was associated with an increased risk of recurrence and disease-related death, but statistically insignificant. (E, F) Triple-negative group: 14-3-3 σ expression was not associated with an increased risk of recurrence. But 14-3-3 σ expression was significantly associated with an increased risk of disease-related death. Dashed line, 14-3-3 σ negative; linear line, 14-3-3 σ positive.
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Figure 4: Disease-free survival and disease-specific survival curves according to 14-3-3 σ expression in each subgroup. (A, C, E) Disease-free survival; (B, D, F) Disease-specific survival. (A, B) Total cases: 14-3-3 σ expression was significantly associated with an increased risk of recurrence and disease-related death. (C, D) Receptor-positive group: 14-3-3 σ expression was associated with an increased risk of recurrence and disease-related death, but statistically insignificant. (E, F) Triple-negative group: 14-3-3 σ expression was not associated with an increased risk of recurrence. But 14-3-3 σ expression was significantly associated with an increased risk of disease-related death. Dashed line, 14-3-3 σ negative; linear line, 14-3-3 σ positive.

Mentions: In both the univariate and multivariate analysis, 14-3-3 σ appeared to be the single most powerful prognostic indicator. Survival curves based on 14-3-3 σ expression also demonstrated a significant correlation between positive 14-3-3 σ expression and adverse clinical outcome of the patients (Figure 4A and 4B). This correlation appeared to be more pronounced in the triple-negative group (Figure 4E and 4F) than in the receptor-positive group (Figure 4C and 4D). In the receptor-positive group, the difference between the 14-3-3 σ positive group and negative group was not statistically significant.


The role and regulatory mechanism of 14-3-3 sigma in human breast cancer.

Ko S, Kim JY, Jeong J, Lee JE, Yang WI, Jung WH - J Breast Cancer (2014)

Disease-free survival and disease-specific survival curves according to 14-3-3 σ expression in each subgroup. (A, C, E) Disease-free survival; (B, D, F) Disease-specific survival. (A, B) Total cases: 14-3-3 σ expression was significantly associated with an increased risk of recurrence and disease-related death. (C, D) Receptor-positive group: 14-3-3 σ expression was associated with an increased risk of recurrence and disease-related death, but statistically insignificant. (E, F) Triple-negative group: 14-3-3 σ expression was not associated with an increased risk of recurrence. But 14-3-3 σ expression was significantly associated with an increased risk of disease-related death. Dashed line, 14-3-3 σ negative; linear line, 14-3-3 σ positive.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4197350&req=5

Figure 4: Disease-free survival and disease-specific survival curves according to 14-3-3 σ expression in each subgroup. (A, C, E) Disease-free survival; (B, D, F) Disease-specific survival. (A, B) Total cases: 14-3-3 σ expression was significantly associated with an increased risk of recurrence and disease-related death. (C, D) Receptor-positive group: 14-3-3 σ expression was associated with an increased risk of recurrence and disease-related death, but statistically insignificant. (E, F) Triple-negative group: 14-3-3 σ expression was not associated with an increased risk of recurrence. But 14-3-3 σ expression was significantly associated with an increased risk of disease-related death. Dashed line, 14-3-3 σ negative; linear line, 14-3-3 σ positive.
Mentions: In both the univariate and multivariate analysis, 14-3-3 σ appeared to be the single most powerful prognostic indicator. Survival curves based on 14-3-3 σ expression also demonstrated a significant correlation between positive 14-3-3 σ expression and adverse clinical outcome of the patients (Figure 4A and 4B). This correlation appeared to be more pronounced in the triple-negative group (Figure 4E and 4F) than in the receptor-positive group (Figure 4C and 4D). In the receptor-positive group, the difference between the 14-3-3 σ positive group and negative group was not statistically significant.

Bottom Line: 14-3-3 sigma (σ) 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).Positive 14-3-3 σ expression was significantly correlated with poor prognosis: disease-free survival (p=0.008) and disease-specific survival (p=0.009).However, the inactivation of 14-3-3 σ is probably achieved mainly by hypermethylation.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Cheil General Hospital & Women's Health Care Center, Catholic Kwandong University College of Medicine, Seoul, Korea.

ABSTRACT

Purpose: 14-3-3 sigma (σ) 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 σ 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 σ protein. The methylation status of the 14-3-3 σ promoter was also evaluated by methylation-specific polymerase chain reaction (PCR). The expression of Efp and 14-3-3 σ 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 σ. The Efp-positive human breast cancers were more frequently 14-3-3 σ-negative (60.5% vs. 39.5%). Hypermethylation of 14-3-3 σ was common (64.9%) and had an inverse association with 14-3-3 σ positivity (p=0.072). Positive 14-3-3 σ 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 σ may involve two mechanisms: ubiquitin-mediated proteolysis by Efp and downregulation by hypermethylation. However, the inactivation of 14-3-3 σ is probably achieved mainly by hypermethylation. Interestingly, 14-3-3 σ 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 σ in breast cancer.

No MeSH data available.


Related in: MedlinePlus