| Summary: | Estrogen receptor alpha (ER) and progesterone receptor (PR) play critical roles in breast cancer, however the clinical value of PR is controversial and it is unclear how PR modulates estrogen signaling. This study reports that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin are genomic agonists as they regulate genes in similar directions but with differing intensities of gene expression and with varying functional annotation of the genes induced. Similarly, in isolation, progestin is a weak phenotypic agonist of estrogen action, however, in the presence of both hormones, progestin antagonizes estrogen-regulated processes and it behaves as a phenotypic antagonist of estrogen. This principle of genomic agonism and phenotypic antagonism rationalizes the good prognosis associated with PR-positivity of ER+ tumors. Importantly, when both the hormones are present, progestin dominates estrogen action such that the levels of transcriptomes, cellular processes and receptor recruitment observed with joint activation of ER and PR correlate with those observed with PR alone, but not ER alone. Despite the correlation, the transcriptomes on dual treatments are optimally different from individual treatments such that the ingenuity analyses predicted antagonism of oncogenic processes and indicated major tumor suppressive functions of concerted but not individual activity of these receptors. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers and sites that link PR and ER/PR complexes. BRCA1 binding motifs were highly enriched at the binding sites of ER/PR complexes, thus implicating a potential role for BRCA1 in ER/PR crosstalk. Additionally, PR isoform-specific reprogramming of ER chromatin binding highlighted pro- and anti-tumorigenic effects of PR in breast cancer. The two PR isoforms PRA and PRB differentially remodel ER binding. PRA/PRB heterodimers expand ER chromatin binding events fourfold, while PRA primarily decreases ER binding by 75% and PRB redistributes ER binding. PR is frequently lost in ER+ milieu due to hypermethylation and copy number loss of its gene locus and loss of PR independently modulates the prognostic value of ER. The well-known prognostic value of ER depends on the presence and activity of PR. While combination therapy with PR agonist and tamoxifen is reported to result in cytostatic inhibition of tumor growth, this study reports that joint therapies using PR antagonist lead to cytotoxic tumor regression. PR potentiates the value of ER since synergy between various PR-antagonists such as CDB4124, CDB4453 or EC313 and tamoxifen results in a remarkable regression of ER+/PR+ T47D xenografts, while individual therapies inhibit tumor growth without regression. In conclusion, the present study provides mechanistic explanations for how PR contributes to the clinical value of ER and it strongly implicates the use of PR both as a prognostic/predictive biomarker and as a therapeutic target in ER+/PR+ breast cancers.
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