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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

Expression of estrogen-responsive ring finger protein (Efp) and 14-3-3 σ in breast cancer. An estrogen receptor-positive breast cancer was positive to Efp (A) and negative to 14-3-3 σ (B) while a triple-negative breast cancer was negative to Efp (C) and positive to 14-3-3 σ (D) (NovaRed with Hematoxylin counterstain, ×400).
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Figure 2: Expression of estrogen-responsive ring finger protein (Efp) and 14-3-3 σ in breast cancer. An estrogen receptor-positive breast cancer was positive to Efp (A) and negative to 14-3-3 σ (B) while a triple-negative breast cancer was negative to Efp (C) and positive to 14-3-3 σ (D) (NovaRed with Hematoxylin counterstain, ×400).

Mentions: Both Efp and 14-3-3 σ showed cytoplasmic staining patterns. 14-3-3 σ was strongly expressed in the myoepithelial cells. In the normal breast epithelial cells, Efp was only weakly positive. About two-thirds of the total tumors (146/217 cases, 67.3%) were negative for both Efp and 14-3-3 σ. About one-third of the total cases (71/217 cases, 32.7%) were positive for at least one of the two genes. Fifty-four of 217 cases (24.9%) were positive for only one of the two genes, while only 17 of 217 cases (7.8%) showed positive staining for both. For the cases when at least one gene was positive, the majority (54/71 cases, 76%) demonstrated a mutually exclusive pattern of positivity, i.e., positive to only one of the two proteins (Table 3, Figure 2). Only 17 cases (23.9%) of the positive 71 cases were positive for both Efp and 14-3-3 σ. The Efp-positive cases were more frequently negative (26/43 cases, 60.5%) for 14-3-3 σ than positive (17/43 cases, 39.5%).


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)

Expression of estrogen-responsive ring finger protein (Efp) and 14-3-3 σ in breast cancer. An estrogen receptor-positive breast cancer was positive to Efp (A) and negative to 14-3-3 σ (B) while a triple-negative breast cancer was negative to Efp (C) and positive to 14-3-3 σ (D) (NovaRed with Hematoxylin counterstain, ×400).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Expression of estrogen-responsive ring finger protein (Efp) and 14-3-3 σ in breast cancer. An estrogen receptor-positive breast cancer was positive to Efp (A) and negative to 14-3-3 σ (B) while a triple-negative breast cancer was negative to Efp (C) and positive to 14-3-3 σ (D) (NovaRed with Hematoxylin counterstain, ×400).
Mentions: Both Efp and 14-3-3 σ showed cytoplasmic staining patterns. 14-3-3 σ was strongly expressed in the myoepithelial cells. In the normal breast epithelial cells, Efp was only weakly positive. About two-thirds of the total tumors (146/217 cases, 67.3%) were negative for both Efp and 14-3-3 σ. About one-third of the total cases (71/217 cases, 32.7%) were positive for at least one of the two genes. Fifty-four of 217 cases (24.9%) were positive for only one of the two genes, while only 17 of 217 cases (7.8%) showed positive staining for both. For the cases when at least one gene was positive, the majority (54/71 cases, 76%) demonstrated a mutually exclusive pattern of positivity, i.e., positive to only one of the two proteins (Table 3, Figure 2). Only 17 cases (23.9%) of the positive 71 cases were positive for both Efp and 14-3-3 σ. The Efp-positive cases were more frequently negative (26/43 cases, 60.5%) for 14-3-3 σ than positive (17/43 cases, 39.5%).

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