@article{THESIS,
      recid = {728},
      author = {Singhal, Hari},
      title = {Genomic Agonism and Phenotypic Antagonism between Estrogen  and Progesterone Receptors Inform Breast Cancer Prognosis  and Therapies},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2016-03},
      number = {THESIS},
      pages = {114},
      abstract = {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.},
      url = {http://knowledge.uchicago.edu/record/728},
}