Journal Article

Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation

Ravo, Maria, Schroth, Gary P, Giurato, Giorgio, Nassa, Giovanni, Ferraro, Lorenzo, Tarallo, Roberta, De Filippo, Maria Rosaria, Benes, Vladimir, Grober, Oli MV, Mutarelli, Margherita, Luo, Shujun, Papa, Maria Francesca, Weisz, Alessandro, Cicatiello, Luigi, Paris, Ornella

2011

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animal Genetics and Genomics / Binding Sites - genetics / Biomedical and Life Sciences / Breast cancer / Cell growth / Cell Line, Tumor / Cell Proliferation / Chromatin Immunoprecipitation / Colleges & universities / Development and progression / Estrogen / Estrogen Receptor alpha - genetics / Estrogen Receptor alpha - metabolism / Estrogen Receptor beta - genetics / Estrogen Receptor beta - metabolism / Estrogens / Gene expression / Gene Expression Regulation, Neoplastic - genetics / Gene Expression Regulation, Neoplastic - physiology / Genetic regulation / Genomes / Genomics / Humans / Immunoblotting / Life Sciences / Ligands / Medical research / Microarrays / Microbial Genetics and Genomics / Oligonucleotide Array Sequence Analysis / Plant Genetics and Genomics / Protein binding / Protein Binding - genetics / Proteomics / Receptors / Research Article / Signal transduction / Transcriptomic methods