Regulation of estrogen receptor β1 expression in breast cancer by epigenetic modification of the 5' regulatory region

Hakeemah Al-Nakhle, Laura Smith, Sandra M. Bell, Philip A. Burns, Michele Cummings, Andrew M. Hanby, Sally Lane, Marie D. Parker, Thomas A. Hughes, Valerie Speirs

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

ERβ1 is often down-regulated in breast cancer compared to normal breast but mechanisms surrounding this are unclear. We examined whether loss of heterozygosity (LOH) or methylation at ERβ promoters (0N, 0K) and/or untranslated exon 0N were involved in ERβ down-regulation in breast cancer tissues and cell lines and if treatment with the de-methylating agent 5-aza-deoxycytidine and/or the histone deacetylase inhibitor Trichostatin A could influence expression in vitro. We found no evidence of correlation between LOH at 14q22-24 (genomic locus containing ERβ/ESR2), and ERβ1 expression in primary breast cancers. A negative correlation between ERβ1 mRNA expression and methylation status was observed for promoter 0N in BT-20, MDA-MB-453 and T47D cells. Promoter 0K was consistently unmethylated. In primary breast tumours, methylation of the untranslated exon 0N, downstream of promoter 0N, but not of promoter 0N itself, correlated with down-regulation of ERβ. In MDA-MB-453 cells, treatment with 5-aza-deoxycytidine was sufficient to induce ERβ1 expression from the 0N promoter while in BT-20 both agents were required. Examination of various sites on ESR2 highlighted epigenetic but not genetic regulation of ERβ1. In particular methylation adjacent to promoter 0N was a key regulatory event for ERβ1 silencing. A combination of de-methylating agents and histone deacetylase inhibitors fully restored ERβ1 expression which may offer a novel therapeutic angle for breast cancer management.

Original languageEnglish
Pages (from-to)2039-2045
Number of pages7
JournalInternational Journal of Oncology
Volume43
Issue number6
Early online date25 Sep 2013
DOIs
Publication statusPublished - Dec 2013

Keywords

  • breast cancer
  • ESR2
  • estrogen receptor β1
  • methylation
  • loss of heterozygosity

Fingerprint Dive into the research topics of 'Regulation of estrogen receptor β1 expression in breast cancer by epigenetic modification of the 5' regulatory region'. Together they form a unique fingerprint.

  • Cite this

    Al-Nakhle, H., Smith, L., Bell, S. M., Burns, P. A., Cummings, M., Hanby, A. M., Lane, S., Parker, M. D., Hughes, T. A., & Speirs, V. (2013). Regulation of estrogen receptor β1 expression in breast cancer by epigenetic modification of the 5' regulatory region. International Journal of Oncology, 43(6), 2039-2045. https://doi.org/10.3892/ijo.2013.2112