Article

Estrogen receptor alpha represses transcription of early target genes via p300 and CtBP1.

Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801-3704, USA.
Molecular and Cellular Biology (Impact Factor: 5.04). 03/2009; 29(7):1749-59. DOI: 10.1128/MCB.01476-08
Source: PubMed

ABSTRACT The regulation of gene expression by nuclear receptors controls the phenotypic properties and diverse biologies of target cells. In breast cancer cells, estrogen receptor alpha (ERalpha) is a master regulator of transcriptional stimulation and repression, yet the mechanisms by which agonist-bound ERalpha elicits repression are poorly understood. We analyzed early estrogen-repressed genes and found that ERalpha is recruited to ERalpha binding sites of these genes, albeit more transiently and less efficiently than for estrogen-stimulated genes. Of multiple cofactors studied, only p300 was recruited to ERalpha binding sites of repressed genes, and its knockdown prevented estrogen-mediated gene repression. Because p300 is involved in transcription initiation, we tested whether ERalpha might be trying to stimulate transcription at repressed genes, with ultimately failure and a shift to a repressive program. We found that estrogen increases transcription in a rapid but transient manner at early estrogen-repressed genes but that this is followed by recruitment of the corepressor CtBP1, a p300-interacting partner that plays an essential role in the repressive process. Thus, at early estrogen-repressed genes, ERalpha initiates transient stimulation of transcription but fails to maintain the transcriptional process observed at estrogen-stimulated genes; rather, it uses p300 to recruit CtBP1-containing complexes, eliciting chromatin modifications that lead to transcriptional repression.

Download full-text

Full-text

Available from: Zeynep Madak Erdogan, Jul 06, 2015
1 Follower
 · 
130 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Estrogen receptor (ER) is a hormone-regulated transcription factor that controls cell division and differentiation in the ovary, breast, and uterus. The expression of ER is a common feature of the majority of breast cancers, which is used as a therapeutic target. Recent genetic studies have shown that ER binding occurs in regions distant to the promoters of estrogen target genes. These studies have also demonstrated that ER binding is accompanied with the binding of other transcription factors, which regulate the function of ER and response to anti-estrogen therapies. In this review, we explain how these factors influence the interaction of ER to chromatin and their cooperation for ER transcriptional activity. Moreover, we describe how the expression of these factors dictates the response to anti-estrogen therapies. Finally, we discuss how cytoplasmatic signaling pathways may modulate the function of ER and its cooperating transcription factors.
    Chromosoma 11/2012; 122(1-2). DOI:10.1007/s00412-012-0392-7 · 3.26 Impact Factor
  • Source
    Breast Cancer - Focusing Tumor Microenvironment, Stem cells and Metastasis, 12/2011; , ISBN: 978-953-307-766-6
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Estrogen receptor-α (ERα, ESR1) is a pivotal transcriptional regulator of breast cancer physiology and is targeted by endocrine therapies. Loss of ERα activity or expression is an indication of endocrine resistance and is associated with increased risk of tumor recurrence and worse prognosis. In this study, we sought to investigate whether elements of the tumor microenvironment, namely macrophages, would impact on ERα and we found that macrophage-derived factors caused loss of ERα expression in breast cancer cells. Conditioned media from macrophages caused activation of several intracellular pathways in breast cancer cells of which c-Src, protein kinase c and mitogen-activated protein kinase (MAPK) were essential for loss of ERα expression. Moreover, a prolonged hyperactivation of MAPK was observed. The activation of this kinase cascade resulted in recruitment of extracellular signal regulated kinase 2 (ERK2) directly to chromatin at the ESR1 gene locus in a process that was dependent upon activation and recruitment of the c-Jun transcription factor. Thus, we identify a novel mechanism for loss of ERα expression in breast cancer cells via macrophage activation of kinase cascades in the cancer cells causing transcriptional repression of the ESR1 gene by a direct chromatin action of a c-Jun/ERK2 complex. The findings in this study support an alternative mechanism, not intrinsic to the tumor cell but derived from the cross-talk with the tumor microenvironment, that could lead to endocrine resistance and might be targeted therapeutically to prevent loss of ERα expression in breast tumors.
    Oncogene 08/2011; 31(14):1825-34. DOI:10.1038/onc.2011.370 · 8.56 Impact Factor