期刊
SCIENCE ADVANCES
卷 2, 期 6, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.1501924
关键词
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资金
- Virginia and D. K. Ludwig Fund for Cancer Research
- Susan G. Komen Postdoctoral Fellowship [PDF12230862]
- National Health and Medical Research Council of Australia [1084416]
- Cancer Australia/National Breast Cancer Foundation [CA1043497]
- National Breast Cancer Foundation [PS-15-041]
- Cancer Prevention and Research Institute of Texas [CPRIT DP150096]
- Department of Defense [W81XWH-13-2-0093, W81XWH-12-1-0288]
- U.S. Department of Defense Breast Cancer Research Program [W81XWH-11-1-0592]
- Royal Adelaide Hospital Research Foundation
- National Breast Cancer Foundation [PS-15-041] Funding Source: researchfish
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.
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