Methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer.

Downregulation of the tight junction protein claudin 1 is a frequent event in breast cancer and is associated with recurrence, metastasis, and reduced survival, suggesting a tumor suppressor role for this protein. Tumor suppressor genes are often epigenetically silenced in cancer. Downregulation of...

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Main Authors: Francescopaolo Di Cello, Leslie Cope, Huili Li, Jana Jeschke, Wei Wang, Stephen B Baylin, Cynthia A Zahnow
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2013-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3701071?pdf=render
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spelling doaj-013937b364da4a229a86a2f99f00f0262020-11-25T02:15:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0187e6863010.1371/journal.pone.0068630Methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer.Francescopaolo Di CelloLeslie CopeHuili LiJana JeschkeWei WangStephen B BaylinCynthia A ZahnowDownregulation of the tight junction protein claudin 1 is a frequent event in breast cancer and is associated with recurrence, metastasis, and reduced survival, suggesting a tumor suppressor role for this protein. Tumor suppressor genes are often epigenetically silenced in cancer. Downregulation of claudin 1 via DNA promoter methylation may thus be an important determinant in breast cancer development and progression. To investigate if silencing of claudin 1 has an epigenetic etiology in breast cancer we compared gene expression and methylation data from 217 breast cancer samples and 40 matched normal samples available through the Cancer Genome Atlas (TCGA). Moreover, we analyzed claudin 1 expression and methylation in 26 breast cancer cell lines. We found that methylation of the claudin 1 promoter CpG island is relatively frequent in estrogen receptor positive (ER+) breast cancer and is associated with low claudin 1 expression. In contrast, the claudin 1 promoter was not methylated in most of the ER-breast cancers samples and some of these tumors overexpress claudin 1. In addition, we observed that the demethylating agents, azacitidine and decitabine can upregulate claudin 1 expression in breast cancer cell lines that have a methylated claudin 1 promoter. Taken together, our results indicate that DNA promoter methylation is causally associated with downregulation of claudin 1 in a subgroup of breast cancer that includes mostly ER+ tumors, and suggest that epigenetic therapy to restore claudin 1 expression might represent a viable therapeutic strategy in this subtype of breast cancer.http://europepmc.org/articles/PMC3701071?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Francescopaolo Di Cello
Leslie Cope
Huili Li
Jana Jeschke
Wei Wang
Stephen B Baylin
Cynthia A Zahnow
spellingShingle Francescopaolo Di Cello
Leslie Cope
Huili Li
Jana Jeschke
Wei Wang
Stephen B Baylin
Cynthia A Zahnow
Methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer.
PLoS ONE
author_facet Francescopaolo Di Cello
Leslie Cope
Huili Li
Jana Jeschke
Wei Wang
Stephen B Baylin
Cynthia A Zahnow
author_sort Francescopaolo Di Cello
title Methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer.
title_short Methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer.
title_full Methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer.
title_fullStr Methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer.
title_full_unstemmed Methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer.
title_sort methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2013-01-01
description Downregulation of the tight junction protein claudin 1 is a frequent event in breast cancer and is associated with recurrence, metastasis, and reduced survival, suggesting a tumor suppressor role for this protein. Tumor suppressor genes are often epigenetically silenced in cancer. Downregulation of claudin 1 via DNA promoter methylation may thus be an important determinant in breast cancer development and progression. To investigate if silencing of claudin 1 has an epigenetic etiology in breast cancer we compared gene expression and methylation data from 217 breast cancer samples and 40 matched normal samples available through the Cancer Genome Atlas (TCGA). Moreover, we analyzed claudin 1 expression and methylation in 26 breast cancer cell lines. We found that methylation of the claudin 1 promoter CpG island is relatively frequent in estrogen receptor positive (ER+) breast cancer and is associated with low claudin 1 expression. In contrast, the claudin 1 promoter was not methylated in most of the ER-breast cancers samples and some of these tumors overexpress claudin 1. In addition, we observed that the demethylating agents, azacitidine and decitabine can upregulate claudin 1 expression in breast cancer cell lines that have a methylated claudin 1 promoter. Taken together, our results indicate that DNA promoter methylation is causally associated with downregulation of claudin 1 in a subgroup of breast cancer that includes mostly ER+ tumors, and suggest that epigenetic therapy to restore claudin 1 expression might represent a viable therapeutic strategy in this subtype of breast cancer.
url http://europepmc.org/articles/PMC3701071?pdf=render
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