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      RhoB modifies estrogen responses in breast cancer cells by influencing expression of the estrogen receptor

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          Abstract

          Introduction

          RhoB has been reported to exert positive and negative effects on cancer pathophysiology but an understanding of its role in breast cancer remains incomplete. Analysis of data from the Oncomine database showed a positive correlation between RhoB expression and positivity for both estrogen receptor alpha (ERα) and progesterone receptor (PR).

          Methods

          This finding was validated by our analysis of a tissue microarray constructed from a cohort of 113 patients and then investigated in human cell models.

          Results

          We found that RhoB expression in tissue was strongly correlated with ERα and PR expression and inversely correlated with tumor grade, tumor size and count of mitosis. In human breast cancer cell lines, RhoB attenuation was associated with reduced expression of both ERα and PR, whereas elevation of RhoB was found to be associated with ERα overexpression. Mechanistic investigations suggested that RhoB modulates ERα expression, controlling both its protein and mRNA levels, and that RhoB modulates PR expression by accentuating the recruitment of ERα and other major co-regulators to the promoter of PR gene. A major consequence of RhoB modulation was that RhoB differentially regulated the proliferation of breast cancer cell lines. Interestingly, we documented crosstalk between RhoB and ERα, with estrogen treatment leading to RhoB activation.

          Conclusion

          Taken together, our findings offer evidence that in human breast cancer RhoB acts as a positive function to promote expression of ERα and PR in a manner correlated with cell proliferation.

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          Most cited references40

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          Biological determinants of endocrine resistance in breast cancer.

          Endocrine therapies targeting oestrogen action (anti-oestrogens, such as tamoxifen, and aromatase inhibitors) decrease mortality from breast cancer, but their efficacy is limited by intrinsic and acquired therapeutic resistance. Candidate molecular biomarkers and gene expression signatures of tamoxifen response emphasize the importance of deregulation of proliferation and survival signalling in endocrine resistance. However, definition of the specific genetic lesions and molecular processes that determine clinical endocrine resistance is incomplete. The development of large-scale computational and genetic approaches offers the promise of identifying the mediators of endocrine resistance that may be exploited as potential therapeutic targets and biomarkers of response in the clinic.
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            Genome-wide analysis of estrogen receptor binding sites.

            The estrogen receptor is the master transcriptional regulator of breast cancer phenotype and the archetype of a molecular therapeutic target. We mapped all estrogen receptor and RNA polymerase II binding sites on a genome-wide scale, identifying the authentic cis binding sites and target genes, in breast cancer cells. Combining this unique resource with gene expression data demonstrates distinct temporal mechanisms of estrogen-mediated gene regulation, particularly in the case of estrogen-suppressed genes. Furthermore, this resource has allowed the identification of cis-regulatory sites in previously unexplored regions of the genome and the cooperating transcription factors underlying estrogen signaling in breast cancer.
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              Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter.

              Transcriptional activation of a gene involves an orchestrated recruitment of components of the basal transcription machinery and intermediate factors, concomitant with an alteration in local chromatin structure generated by posttranslational modifications of histone tails and nucleosome remodeling. We provide here a comprehensive picture of events resulting in transcriptional activation of a gene, through evaluating the estrogen receptor-alpha (NR3A1) target pS2 gene promoter in MCF-7 cells. This description integrates chromatin remodeling with a kinetic evaluation of cyclical networks of association of 46 transcription factors with the promoter, as determined by chromatin immunoprecipitation assays. We define the concept of a "transcriptional clock" that directs and achieves the sequential and combinatorial assembly of a transcriptionally productive complex on a promoter. Furthermore, the unanticipated findings of key roles for histone deacetylases and nucleosome-remodeling complexes in limiting transcription implies that transcriptional activation is a cyclical process that requires both activating and repressive epigenetic processes.
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                Author and article information

                Contributors
                Journal
                Breast Cancer Res
                Breast Cancer Res
                Breast Cancer Research : BCR
                BioMed Central
                1465-5411
                1465-542X
                2013
                22 January 2013
                : 15
                : 1
                : R6
                Affiliations
                [1 ]INSERM U563 and UMR1037, Institut Claudius Regaud, 20-24 rue du pont St Pierre, Toulouse cedex 31052, France
                [2 ]Faculté des Sciences Pharmaceutiques, Université Paul Sabatier Toulouse III, Toulouse cedex 31062, France
                [3 ]EA4553, Institut Claudius Regaud, 20-24 rue du pont St Pierre, Toulouse cedex 31052, France
                [4 ]Département de Biologie et de Pathologie, Institut Claudius Regaud, 20-24 rue du pont St Pierre, Toulouse cedex 31052, France
                [5 ]Tumorbiologischen Labor, Klinikum der Ludwig-Maximilians-Universität, Maistraße 11, München 80337, Germany
                Article
                bcr3377
                10.1186/bcr3377
                3672819
                23339407
                2fa93838-8140-471f-a396-58959275afe1
                Copyright © 2013 Médale-Giamarchi et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 6 August 2012
                : 22 November 2012
                : 10 January 2013
                Categories
                Research Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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