Lack of RUNX3 inactivation in columnar cell lesions of breast

Subramaniam, Manish Mani; Chan, Jason Yongsheng; Omar, Mohd Feroz Mohd; Ito, Kosei; Ito, Yoshiaki; Yeoh, Khay Guan; Salto-Tellez, Manuel; Putti, Thomas Choudary

doi:10.1111/j.1365-2559.2010.03675.x

Cited by 5 publications

(1 citation statement)

References 48 publications

(137 reference statements)

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“… 11 – 15 Downregulation of RUNX3 protein by promoter methylation (hypermethylation) has been found to play an important role in epithelial tumorigenesis and epithelial-mesenchymal transition of several malignancies including BC. 11 , 15 – 21 RUNX3 also inhibits the estrogen-dependent proliferation, transformation, and the tumorigenicity of BC cells in severe combined immunodeficiency mice. 22 Of female RUNX3 (+/−) mice, 20% spontaneously developed ductal carcinoma at an average age of 14.5 months, indicating that RUNX3 acts as a novel tumor suppressor in BC.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological significance and potential drug target of RUNX3 in breast cancer

Yu¹,

Chen²,

Kong³

et al. 2014

DDDT

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BackgroundPrevious reports indicate that RUNX3 is a tumor suppressor in several types of human tumors, including breast cancer (BC). However, the correlation between RUNX3 hypermethylation and the incidence of BC remains unclear. In this study, we conducted a systematic review and meta-analysis aiming to comprehensively assess the potential role of RUNX3 hypermethylation in the pathogenesis of BC.MethodsA detailed literature search was made to identify studies for related research publications. Methodological quality of the studies was evaluated. Analysis of pooled data was performed. Odds ratio (OR) was calculated and summarized respectively.ResultsFinal analysis of 565 BC patients from eleven eligible studies was performed. The results showed that RUNX3 hypermethylation was significantly higher in BC than in normal breast tissue, the pooled OR from nine studies including 339 BC and 248 normal breast tissue (OR =24.12, 95% confidence interval [CI] =13.50–43.11, Z=10.75, P<0.00001). Further analysis also showed significantly increased OR of RUNX3 hypermethylation in estrogen receptor (ER)-positive than in ER-negative BC patients (OR =5.67, 95% CI =2.69–11.95, Z=4.57, P<0.00001). In addition, RUNX3 messenger RNA (mRNA) high expression was found to be correlated to better overall survival in 3,455 cases of BC patients that were followed up for 20 years (hazard ratio [HR] 0.79, P=8.8×10−5). Interestingly, RUNX3 mRNA overexpression was found to be correlated to better overall survival in only 668 cases of ER-negative patients (HR 0.72, P=0.01), but not in 1,767 cases of ER-positive patients (HR 0.87, P=0.13).ConclusionThe results of this meta-analysis suggest that RUNX3 hypermethylation may be implicated in the pathogenesis of BC. Detection of RUNX3 mRNA may be a helpful and valuable biomarker for diagnosis of BC, especially in ER-negative BC. We also discussed the significance of RUNX3 as a potential drug target.

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Section: Introductionmentioning

confidence: 99%

Clinicopathological significance and potential drug target of RUNX3 in breast cancer

Yu¹,

Chen²,

Kong³

et al. 2014

DDDT

View full text Add to dashboard Cite

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Targeting the Epigenome as a Novel Therapeutic Approach for Breast Cancer

et al. 2017

Advances in Experimental Medicine and Biology

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Breast cancer is one of complex diseases that are influenced by environment. Various genetic and epigenetic alterations are provoking causes of breast carcinogenesis. Dynamic epigenetic regulation including DNA methylation and histone modification induces dysregulation of genes related to proliferation, apoptosis, and metastasis in breast cancer. DNA methylation is strongly associated with the repression of transcription through adding to the methyl group by DNA methyltransferases (DNMTs), and tumor suppressor genes such as CCND2 and RUNX3 have been investigated to undergo hypermethylation at promoter region in breast cancer. In addition, histone deacetylases (HDACs) contribute to transcriptional repression by removing acetyl group at lysine residues leading to tumorigenesis. Since epigenetic changes are reversible, therapeutic approaches have been applied with epigenetic modification drugs such as DNMT inhibitors and HDAC inhibitors. In this chapter, we will summarize the feature of epigenetic markers in breast cancer cells and the effect of single or combination of epigenetic reagents for breast cancer therapy.

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Epigenetic progression of columnar cell lesions of the breast to invasive breast cancer

Verschuur-Maes

Bruin

Diest

2012

Breast Cancer Res Treat

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Promoter hypermethylation of several tumour suppressor genes often occurs during breast carcinogenesis, but little is known about epigenetic silencing in the possible precursor columnar cell lesion (CCL). Promoter hypermethylation of 50 different tumour suppressor genes was assessed in normal breast tissue (N = 10), CCL (N = 15), ductal carcinoma in situ (DCIS) grade I originating in CCL (N = 5) and paired CCL (N = 15) with DCIS (N = 7) and/or invasive carcinoma (N = 14) by Methylation-specific multiplex ligation-dependent probe amplification. Increasing mean cumulative methylation levels were found from normal breast tissue to CCL to DCIS and invasive carcinoma (P < 0.001) with similar methylation levels in DCIS and invasive carcinoma. Methylation levels and frequencies (in the overall analysis and analysis of only the synchronous lesions) were the highest for RASSF1, CCND2, ID4, SCGB3A1 and CDH13. The methylation levels of ID4, CCND2, and CDH13 increased significantly from normal breast tissue to CCL and to DCIS/invasive carcinoma. RASSF1, SCGB3A1 and SFRP5 had significant higher methylation levels in CCL compared to normal breast tissue, but showed no significant differences between CCL, DCIS and invasive carcinoma. Also, no difference was found between CCLs with and without atypia, or CCLs with or without synchronous cancer. In conclusion, promoter hypermethylation for several established tumour suppressor genes is already present in CCLs, underlining that promoter hypermethylation is an early event in breast carcinogenesis. Atypia in CCL or the presence of synchronous more advanced lesions does not seem to be accompanied by higher methylation levels.

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Lack of RUNX3 inactivation in columnar cell lesions of breast

Abstract: RUNX3 inactivation occurs specifically in DCIS and IDC cells. In addition, RUNX3 inactivation may not be a common association between CCLs and breast carcinomas.

Cited by 5 publications

References 48 publications

Clinicopathological significance and potential drug target of RUNX3 in breast cancer

Clinicopathological significance and potential drug target of RUNX3 in breast cancer

Targeting the Epigenome as a Novel Therapeutic Approach for Breast Cancer

Epigenetic progression of columnar cell lesions of the breast to invasive breast cancer

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Lack of RUNX3 inactivation in columnar cell lesions of breast

Abstract: RUNX3 inactivation occurs specifically in DCIS and IDC cells. In addition, RUNX3 inactivation may not be a common association between CCLs and breast carcinomas.

Cited by 5 publications

References 48 publications

Clinicopathological significance and potential drug&nbsp;target of RUNX3 in breast cancer

Clinicopathological significance and potential drug&nbsp;target of RUNX3 in breast cancer

Targeting the Epigenome as a Novel Therapeutic Approach for Breast Cancer

Epigenetic progression of columnar cell lesions of the breast to invasive breast cancer

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Product

Resources

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Clinicopathological significance and potential drug target of RUNX3 in breast cancer

Clinicopathological significance and potential drug target of RUNX3 in breast cancer