@article{TEXTUAL,
      recid = {11058},
      author = {Singhal, Hari and Greene, Marianne E. and Tarulli, Gerard  and Zarnke, Allison L. and Bourgo, Ryan J. and Laine,  Muriel and Chang, Ya-Fang and Ma, Shihong and Dembo, Anna  G. and Raj, Ganesh V. and Hickey, Theresa E. and Tilley,  Wayne D. and Greene, Geoffrey L.},
      title = {Genomic agonism and phenotypic antagonism between estrogen  and progesterone receptors in breast cancer},
      journal = {Science Advances},
      address = {2016-06-24},
      number = {TEXTUAL},
      abstract = {The functional role of progesterone receptor (PR) and its  impact on estrogen signaling in breast cancer remain  controversial. In primary ER<sup>+</sup> (estrogen  receptor-positive)/PR<sup>+</sup> 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  observedwith 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 PRmodulator/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<sup>+</sup>/PR<sup>+</sup> breast cancers should be  explored.},
      url = {http://knowledge.uchicago.edu/record/11058},
}