Progesterone receptor B (PRB) promoter hypermethylation in sporadic breast cancer

Cormack, Orla Mc; Chung, Wen Yuan; Fitzpatrick, Patricia; Cooke, Fiachra; Flynn, B.; Harrison, Matthew; Fox, Edward J.; Gallagher, Emma; McGoldrick, Aloysius; Dervan, P.; McCann, Amanda; Kerin, Michael J.

doi:10.1007/s10549-007-9757-7

Cited by 18 publications

(14 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results correlate closely with biochemical ligand binding assays and clinical response rates to endocrine therapy 53,54. Furthermore, PR promoter methylation is commonly observed in primary breast cancer cases and may be a mechanism by which this protein is downregulated 55. Importantly, higher PR levels are negatively correlated with tumor size and grade.…”

Section: Introductionsupporting

confidence: 73%

Classical and Novel Prognostic Markers for Breast Cancer and their Clinical Significance

Taneja

Maglic

Kai

et al. 2010

Clin Med Insights Oncol

131

135

View full text Add to dashboard Cite

The use of biomarkers ensures breast cancer patients receive optimal treatment. Established biomarkers such as estrogen receptor (ER) and progesterone receptor (PR) have been playing significant roles in the selection and management of patients for endocrine therapy. HER2 is a strong predictor of response to trastuzumab. Recently, the roles of ER as a negative and HER2 as a positive indicator for chemotherapy have been established. Ki67 has traditionally been recognized as a poor prognostic factor, but recent studies suggest that measurement of Ki67-positive cells during treatment will more effectively predict treatment efficacy for both anti-hormonal and chemotherapy. p53 mutations are found in 20–35% of human breast cancers and are associated with aggressive disease with poor clinical outcome when the DNA-binding domain is mutated. The utility of cyclin D1 as a predictor of breast cancer prognosis is controversial, but cyclin D1b overexpression is associated with poor prognosis. Likewise, overexpression of the low molecular weight form of cyclin E1 protein predicts poor prognosis. Breast cancers from BRCA1/2 carriers often show high nuclear grades, negativity to ER/PR/HER2, and p53 mutations, and thus, are associated with poor prognosis. The prognostic values of other molecular markers, such as p14ARF, TBX2/3, VEGF in breast cancer are also discussed. Careful evaluation of these biomarkers with current treatment modality is required to determine whether their measurement or monitoring offer significant clinical benefits.

show abstract

Section: Introductionsupporting

confidence: 73%

Classical and Novel Prognostic Markers for Breast Cancer and their Clinical Significance

Taneja

Maglic

Kai

et al. 2010

Clin Med Insights Oncol

131

135

View full text Add to dashboard Cite

show abstract

“…Similar results were found by Feng et al (27); however, Gaudet et al reported that PRB (but not PRA ) methylation was a frequent event (92.2%), although the actual levels of methylation were weak (18). Furthermore, another group reports higher frequency of PRB methylation in sporadic breast tumors (26). It should be noted that inconsistency of reported methylation frequencies could be partly due to different sensitivities of methods used for measuring methylation, highlighting the need for standardized assays.…”

Section: Discussionmentioning

confidence: 99%

“…The position of the primers within PRA and PRB genes are shown in Figure 1. The PRB CpG sites have been previously analyzed by others and were found to be associated with expression (25, 26). We found high concordance in methylation between adjacent sites and we therefore used mean values from all pyrosequenced CpG sites as a measure of methylation of a given gene.…”

Section: Methodsmentioning

confidence: 99%

Progesterone Receptor Isoform-Specific Promoter Methylation: Association ofPRAPromoter Methylation with Worse Outcome in Breast Cancer Patients

Pathiraja

Shetty

Jelı́nek

et al. 2011

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, PRA and PRB, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome. Experimental Design We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n=500), and in patients who underwent surgery only (n=500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand binding assay, respectively. Results Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen treated group. Conclusions Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this study shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer.

show abstract

“…Cytosine methylation of DNA at cytosine-guanine dinucleotides and post-translational modifications of histones (including acetylation and methylation) are part of an epigenetic regulatory system that controls the establishment of permissive or repressive chromatin structure. There is increasing evidence, stemming mainly from studies in breast and endometrial cancers, that the expression of PRs can be regulated by certain epigenetic events within the PR gene (Lapidus et al, 1996;Ferguson et al, 1998;Sasaki et al, 2001Sasaki et al, , 2002Sasaki et al, , 2003Liu et al, 2003;Xu et al, 2004;Xiong et al, 2005;Wu et al, 2006;Mc Cormack et al, 2008;Gaudet et al, 2009). Xiong et al (2005) reported that hypermethylation of the PR-B promoter silenced its gene expression in adenocarcinoma cells, which could be restored through DNA demethylation in conjunction with histone acetylation.…”

Section: Introductionmentioning

confidence: 99%

Term myometrium is characterized by increased activating epigenetic modifications at the progesterone receptor-A promoter

Chai

Smith

Zakár

et al. 2012

Molecular Human Reproduction

View full text Add to dashboard Cite

Term human myometrial expression of progesterone receptor (PR)-A is increased relative to PR-B, and as PR-A is a repressor of progesterone action mediated through PR-B, this increase may mediate the withdrawal of progesterone action and precipitate the onset of labour. PR-A and PR-B expression is regulated by two separate promoters of the PR gene. We hypothesized that epigenetic histone modifications at the two promoters contribute to the labour-associated regulation of PR-A and PR-B expression in term myometrium. PR total, PR-B and PR-A mRNA levels were determined using quantitative real-time PCR, and chromatin immunoprecipitation was used to determine the levels of activating and repressive histone modifications at the PR-A and PR-B promoters in human myometrial samples not in labour (n ¼ 4) and in labour (n ¼ 4). Chromatin extracts were immunoprecipitated with antibodies against activating (histone H3 and H4 acetylation and histone H3 lysine 4 trimethylation), and repressive (histone H3 lysine 9 trimethylation, histone H3 lysine 27 trimethylation and asymmetrical histone H3 arginine 2 dimethylation) histone modifications. PR-A mRNA levels increased during labour, while PR-B mRNA levels remained constant resulting in an increase of PR-A/PR-B mRNA ratio, as expected. Regardless of labour status, significantly higher levels of the activating histone modifications were found at the PR-A promoter compared with the PR-B promoter (P , 0.001). H3K4me3 increased significantly at both promoters with labour onset (P ¼ 0.001). Low levels of the repressive histone modifications were also present at both promoters, with no labour-associated changes observed. Our data indicate that the PR-A promoter is epigenetically marked for activation in term myometrium more extensively than the PR-B promoter, and that labour is associated with an increase in H3K4me3 activating modification, consistent with the previously described increase in PR protein at this time.

show abstract

Progesterone receptor B (PRB) promoter hypermethylation in sporadic breast cancer

Abstract: The majority of tumours were methylated for PRB. This did not directly compromise PRB expression suggesting that other factors may down regulate the PR gene. When PRB was expressed, it correlated with good prognostic markers and better overall survival.

Cited by 18 publications

References 18 publications

Classical and Novel Prognostic Markers for Breast Cancer and their Clinical Significance

Classical and Novel Prognostic Markers for Breast Cancer and their Clinical Significance

Progesterone Receptor Isoform-Specific Promoter Methylation: Association ofPRAPromoter Methylation with Worse Outcome in Breast Cancer Patients

Term myometrium is characterized by increased activating epigenetic modifications at the progesterone receptor-A promoter

Contact Info

Product

Resources

About