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  • 1
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    Progesterone receptor modulates ERalpha action in breast cancer (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-07-15
    Description: Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-alpha (ERalpha) function and breast cancer prognosis. Here we show that PR is not merely an ERalpha-induced gene target, but is also an ERalpha-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERalpha to direct ERalpha chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERalpha(+) cell line xenografts and primary ERalpha(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERalpha antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERalpha(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERalpha chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650274/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650274/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mohammed, Hisham -- Russell, I Alasdair -- Stark, Rory -- Rueda, Oscar M -- Hickey, Theresa E -- Tarulli, Gerard A -- Serandour, Aurelien A -- Birrell, Stephen N -- Bruna, Alejandra -- Saadi, Amel -- Menon, Suraj -- Hadfield, James -- Pugh, Michelle -- Raj, Ganesh V -- Brown, Gordon D -- D'Santos, Clive -- Robinson, Jessica L L -- Silva, Grace -- Launchbury, Rosalind -- Perou, Charles M -- Stingl, John -- Caldas, Carlos -- Tilley, Wayne D -- Carroll, Jason S -- 242664/European Research Council/International -- 5P30CA142543/CA/NCI NIH HHS/ -- A10178/Cancer Research UK/United Kingdom -- England -- Nature. 2015 Jul 16;523(7560):313-7. doi: 10.1038/nature14583. Epub 2015 Jul 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK. ; Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, Hanson Institute Building, University of Adelaide, Adelaide, South Australia 5005, Australia. ; Department of Urology, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA. ; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, CB7295, Chapel Hill, North Carolina 27599, USA. ; 1] Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK [2] Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK [3] Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26153859" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/drug therapy/*genetics/*metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chromatin/drug effects/genetics/metabolism ; DNA Copy Number Variations/genetics ; Disease Progression ; Estrogen Receptor alpha/antagonists & inhibitors/*metabolism ; Estrogens/metabolism/pharmacology ; Female ; *Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Ligands ; Mice ; Progesterone/metabolism/pharmacology ; Protein Binding/drug effects ; Receptors, Progesterone/genetics/*metabolism ; Transcription, Genetic/drug effects ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Corrigendum: Progesterone receptor modulates ERalpha action in breast cancer (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-08-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mohammed, Hisham -- Russell, I Alasdair -- Stark, Rory -- Rueda, Oscar M -- Hickey, Theresa E -- Tarulli, Gerard A -- Serandour, Aurelien A -- Birrell, Stephen N -- Bruna, Alejandra -- Saadi, Amel -- Menon, Suraj -- Hadfield, James -- Pugh, Michelle -- Raj, Ganesh V -- Brown, Gordon D -- D'Santos, Clive -- Robinson, Jessica L L -- Silva, Grace -- Launchbury, Rosalind -- Perou, Charles M -- Stingl, John -- Caldas, Carlos -- Tilley, Wayne D -- Carroll, Jason S -- England -- Nature. 2015 Oct 1;526(7571):144. doi: 10.1038/nature14959. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245370" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-06-25
    Description: The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER + (estrogen receptor–positive)/PR + human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER + /PR + breast cancers should be explored.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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