title: 5-Aza-2-deoxycytidine and trichostatin A increase COUP-TFII expression in antiestrogen-resistant breast cancer cell lines.
abstract: COUP-TFII is reduced in endocrine-resistant breast cancer cells and is negatively associated with tumor grade. Transient re-expression of COUP-TFII restores antiestrogen sensitivity in resistant LCC2 and LCC9 cells and repression of COUP-TFII results in antiestrogen-resistance in MCF-7 endocrine-sensitive cells. We addressed the hypothesis that reduced COUP-TFII expression in endocrine-resistant breast cancer cells results from epigenetic modification. The NR2F2 gene encoding COUP-TFII includes seven CpG islands, including one in the 5' promoter and one in exon 1. Treatment of LCC2 and LCC9 endocrine-resistant breast cancer cells with 5-aza-2'-deoxycytidine (AZA), a DNA methyltransferase (DNMT) inhibitor, +/- trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, increased COUP-TFII suggesting that the decrease in COUP-TFII is mediated by epigenetic changes. Methylation-specific PCR (MSP) revealed higher methylation of NR2F2 in the first exon in LCC2 and LCC9 cells compared to MCF-7 cells and AZA reduced this methylation. Translational importance is suggested by Cancer Methylome System (CMS) analysis revealing that breast tumors have increased COUP-TFII (NR2F2) promoter and gene methylation versus normal breast.
authors: Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Numan
authors: N
authors: Al-Rayyan
authors: Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Lacey M
authors: LM
authors: Litchfield
authors: Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Margarita M
authors: MM
authors: Ivanova
authors: Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Brandie N
authors: BN
authors: Radde
authors: Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Alan
authors: A
authors: Cheng
authors: Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors: Ahmed
authors: A
authors: Elbedewy
authors: Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA. Electronic address: carolyn.klinge@louisville.edu.
authors: Carolyn M
authors: CM
authors: Klinge
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D051837:COUP Transcription Factor II / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000235:genetics; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D061986:MCF-7 Cells; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D051837:COUP Transcription Factor II; D000077209:Decitabine; D020847:Estrogen Receptor Modulators; D047629:Estrogen Receptor beta; D006877:Hydroxamic Acids; C012589:trichostatin A; C095569:NR2F2 protein, human
keywords: Breast cancer; COUP-TFII; Endocrine-resistance; Epigenetic modification; Estrogen receptor