Fig. 5. Cytotoxic tumor regression on combination therapy with tamoxifen and PR antagonist CDB4124.

(A) T47D xenografts were grown in ovariectomized nude mice containing estrogen silastic implants and were treated with placebo, tamoxifen, CDB-4124, or tamoxifen plus CDB4124. The average tumor volume at the start of therapies was 125 mm³, and percentage change in tumor volume is shown (n = at least 7). P values are calculated using mixed linear modeling. Control group is plotted until day 49 because a significant number of mice in the control group died after day 49. (B) Genomic agonism: In isolation and in combination, activated ER and PR regulate the expression of most of the genes in similar directions. The magnitude of gene expression on joint estrogen plus progestin treatments correlates with those observed with progestin alone, but not estrogen alone. Phenotypic antagonism: Individually, estrogen and progestin activate most of the oncogenic pathways in similar directions, but progestin lacks the degree of activation induced by estrogen. When both ER and PR are active, PR opposes ER-regulated phenotypes, suggesting phenotypic antagonism between these hormones. (C) Model for ER/PR crosstalk. PR remodels chromatin and redirects ER binding to antagonize estrogen signaling and to potentiate response to antiestrogens. Genomic agonism and the phenotypic antagonism between ER and PR highlight the prognostic and therapeutic value of PR in ER⁺/PR⁺ breast cancers. **<0.005.