title: A New Role for ERα: Silencing via DNA Methylation of Basal, Stem Cell, and EMT Genes.
abstract: Resistance to hormonal therapies is a major clinical problem in the treatment of estrogen receptor α-positive (ERα+) breast cancers. Epigenetic marks, namely DNA methylation of cytosine at specific CpG sites (5mCpG), are frequently associated with ERα+status in human breast cancers. Therefore, ERα may regulate gene expression in part via DNA methylation. This hypothesis was evaluated using a panel of breast cancer cell line models of antiestrogen resistance. Microarray gene expression profiling was used to identify genes normally silenced in ERα+cells but derepressed upon exposure to the demethylating agent decitabine, derepressed upon long-term loss of ERα expression, and resuppressed by gain of ERα activity/expression. ERα-dependent DNA methylation targets (n = 39) were enriched for ERα-binding sites, basal-up/luminal-down markers, cancer stem cell, epithelial-mesenchymal transition, and inflammatory and tumor suppressor genes. Kaplan-Meier survival curve and Cox proportional hazards regression analyses indicated that these targets predicted poor distant metastasis-free survival among a large cohort of breast cancer patients. The basal breast cancer subtype markers LCN2 and IFI27 showed the greatest inverse relationship with ERα expression/activity and contain ERα-binding sites. Thus, genes that are methylated in an ERα-dependent manner may serve as predictive biomarkers in breast cancer.
  
  
  
  ERα directs DNA methylation-mediated silencing of specific genes that have biomarker potential in breast cancer subtypes. Mol Cancer Res; 15(2); 152-64. ©2016 AACR.
authors.affiliation: Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania. jboyd@fiu.edu eric.ariazi@freenome.com.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ariazi
authors.affiliation: Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.
authors.forename: John C
authors.initials: JC
authors.lastname: Taylor
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Black
authors.affiliation: Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Nicolas
authors.affiliation: Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Slifker
authors.affiliation: Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida.
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Azzam
authors.affiliation: Fox Chase Cancer Center, Temple University Health System, Philadelphia, Pennsylvania. jboyd@fiu.edu eric.ariazi@freenome.com.|Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida.
authors.forename: Jeff
authors.initials: J
authors.lastname: Boyd
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000502:physiology*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha