title: Progesterone receptor modulates ERα action in breast cancer.
abstract: Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα 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 ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Hisham
authors.initials: H
authors.lastname: Mohammed
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: I Alasdair
authors.initials: IA
authors.lastname: Russell
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Rory
authors.initials: R
authors.lastname: Stark
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: 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.
authors.forename: Theresa E
authors.initials: TE
authors.lastname: Hickey
authors.affiliation: 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.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Tarulli
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Aurelien A
authors.initials: AA
authors.lastname: Serandour
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Aurelien A A
authors.initials: AA
authors.lastname: Serandour
authors.affiliation: 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.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Birrell
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Bruna
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Amel
authors.initials: A
authors.lastname: Saadi
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Suraj
authors.initials: S
authors.lastname: Menon
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: James
authors.initials: J
authors.lastname: Hadfield
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Pugh
authors.affiliation: Department of Urology, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: D'Santos
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Jessica L L
authors.initials: JL
authors.lastname: Robinson
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, CB7295, Chapel Hill, North Carolina 27599, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Silva
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Launchbury
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, CB7295, Chapel Hill, North Carolina 27599, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: John
authors.initials: J
authors.lastname: Stingl
authors.affiliation: 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.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: 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.
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics; D018450:Disease Progression; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008024:Ligands; D051379:Mice; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D002843:Chromatin; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; D011980:Receptors, Progesterone; D011374:Progesterone