Methylation of the Claudin 1 Promoter Is Associated with Loss of Expression in Estrogen Receptor Positive Breast Cancer

Francescopaolo Di Cello, Leslie Cope, Huili Li, Jana Jeschke, Wei Wang, Stephen B Baylin, Cynthia Zahnow

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere68630
JournalPLoS One
Volume8
Issue number7
DOIs
StatePublished - Jul 3 2013

Fingerprint

Claudin-1
Methylation
Estrogen Receptors
methylation
breast neoplasms
promoter regions
Breast Neoplasms
neoplasms
Tumors
Down-Regulation
epigenetics
decitabine
DNA Methylation
Epigenomics
cell lines
estrogen receptors
Neoplasms
Genes
therapeutics
Zonula Occludens-1 Protein

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Methylation of the Claudin 1 Promoter Is Associated with Loss of Expression in Estrogen Receptor Positive Breast Cancer. / Di Cello, Francescopaolo; Cope, Leslie; Li, Huili; Jeschke, Jana; Wang, Wei; Baylin, Stephen B; Zahnow, Cynthia.

In: PLoS One, Vol. 8, No. 7, e68630, 03.07.2013.

Research output: Contribution to journalArticle

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