Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/105536
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Type: Journal article
Title: Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer
Author: Singhal, H.
Greene, M.
Tarulli, G.
Zarnke, A.
Bourgo, R.
Laine, M.
Chang, Y.-.F.
Ma, S.
Dembo, A.
Raj, G.
Hickey, T.
Tilley, W.
Greene, G.
Citation: Science Advances, 2016; 2(6):e1501924
Publisher: American Association for the Advancement of Science
Issue Date: 2016
ISSN: 2375-2548
2375-2548
Statement of
Responsibility: 
Hari Singhal, Marianne E. Greene, Gerard Tarulli, Allison L. Zarnke, Ryan J. Bourgo, Muriel Laine, Ya-Fang Chang, Shihong Ma, Anna G. Dembo, Ganesh V. Raj, Theresa E. Hickey, Wayne D. Tilley, Geoffrey L. Greene
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.
Keywords: Estrogen; progesterone; breast cancer; chromatin; reprogramming; therapies; agonism; antagonism; prognosis; BRCA1
Rights: 2016 © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
RMID: 0030050659
DOI: 10.1126/sciadv.1501924
Grant ID: http://purl.org/au-research/grants/nhmrc/1084416
Published version: http://advances.sciencemag.org/content/2/6/e1501924
Appears in Collections:Medical Education Unit publications

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