title: Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer.
abstract: 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.
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Hari
authors.initials: H
authors.lastname: Singhal
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Marianne E
authors.identifier: 0000-0001-9048-6910
authors.initials: ME
authors.lastname: Greene
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Gerard
authors.initials: G
authors.lastname: Tarulli
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Allison L
authors.identifier: 0000-0003-1544-4256
authors.initials: AL
authors.lastname: Zarnke
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Bourgo
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Muriel
authors.initials: M
authors.lastname: Laine
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Chang
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75080, USA.
authors.forename: Shihong
authors.initials: S
authors.lastname: Ma
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Anna G
authors.identifier: 0000-0002-6228-9466
authors.initials: AG
authors.lastname: Dembo
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75080, USA.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Theresa E
authors.identifier: 0000-0002-2752-730X
authors.initials: TE
authors.lastname: Hickey
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Greene
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D019398:Genes, BRCA1; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D058990:Molecular Targeted Therapy; D009707:Nucleosomes / Q000378:metabolism; D059372:Nucleotide Motifs; D010641:Phenotype; D011372:Progestins / Q000378:metabolism / Q000494:pharmacology; D011379:Prognosis; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics* / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D002843:Chromatin; D009707:Nucleosomes; D011372:Progestins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen
keywords: BRCA1; Estrogen; agonism; antagonism; breast cancer; chromatin; progesterone; prognosis; reprogramming; therapies