title: Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation.
abstract: BACKGROUND
  Estrogen receptors alpha (ERα) and beta (ERβ) are transcription factors (TFs) that mediate estrogen signaling and define the hormone-responsive phenotype of breast cancer (BC). The two receptors can be found co-expressed and play specific, often opposite, roles, with ERβ being able to modulate the effects of ERα on gene transcription and cell proliferation. ERβ is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease. The identification of the genomic targets of ERβ in hormone-responsive BC cells is thus a critical step to elucidate the roles of this receptor in estrogen signaling and tumor cell biology.
  
  
  RESULTS
  Expression of full-length ERβ in hormone-responsive, ERα-positive MCF-7 cells resulted in a marked reduction in cell proliferation in response to estrogen and marked effects on the cell transcriptome. By ChIP-Seq we identified 9702 ERβ and 6024 ERα binding sites in estrogen-stimulated cells, comprising sites occupied by either ERβ, ERα or both ER subtypes. A search for TF binding matrices revealed that the majority of the binding sites identified comprise one or more Estrogen Response Element and the remaining show binding matrixes for other TFs known to mediate ER interaction with chromatin by tethering, including AP2, E2F and SP1. Of 921 genes differentially regulated by estrogen in ERβ+ vs ERβ- cells, 424 showed one or more ERβ site within 10 kb. These putative primary ERβ target genes control cell proliferation, death, differentiation, motility and adhesion, signal transduction and transcription, key cellular processes that might explain the biological and clinical phenotype of tumors expressing this ER subtype. ERβ binding in close proximity of several miRNA genes and in the mitochondrial genome, suggests the possible involvement of this receptor in small non-coding RNA biogenesis and mitochondrial genome functions.
  
  
  CONCLUSIONS
  Results indicate that the vast majority of the genomic targets of ERβ can bind also ERα, suggesting that the overall action of ERβ on the genome of hormone-responsive BC cells depends mainly on the relative concentration of both ERs in the cell.
authors.affiliation: Department of General Pathology, Second University of Naples, vico L, De Crecchio 7, 80138 Napoli, Italy.
authors.forename: Oli M V
authors.initials: OM
authors.lastname: Grober
authors.forename: Margherita
authors.initials: M
authors.lastname: Mutarelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Giurato
authors.forename: Maria
authors.initials: M
authors.lastname: Ravo
authors.forename: Luigi
authors.initials: L
authors.lastname: Cicatiello
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: De Filippo
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Ferraro
authors.forename: Giovanni
authors.initials: G
authors.lastname: Nassa
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Papa
authors.forename: Ornella
authors.initials: O
authors.lastname: Paris
authors.forename: Roberta
authors.initials: R
authors.lastname: Tarallo
authors.forename: Shujun
authors.initials: S
authors.lastname: Luo
authors.forename: Gary P
authors.initials: GP
authors.lastname: Schroth
authors.forename: Vladimir
authors.initials: V
authors.lastname: Benes
authors.forename: Alessandro
authors.initials: A
authors.lastname: Weisz
mesh_terms: D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta