Crystal structures exist for human, but not rodent, estrogen receptor-α ligand-binding domain (ERα-LBD). Consequently, rodent studies involving binding of compounds to ERα-LBD are limited in their molecular-level interpretation and extrapolation to humans. Because the sequences of rodent and human ERα-LBDs are > 95% identical, we expected their 3D structures and ligand binding to be highly similar. To test this hypothesis, we used the human ERα-LBD structure (PDB 3UUD) as a template to produce rat and mouse homology models. Employing the rodent models and human structure, we generated docking poses of 23 Group A ligands (17ß-estradiol, diethylstilbestrol, and 21 paraben analogs) in AutoDock Vina for interspecies comparisons. Ligand RMSDs (Å) (median, 95% CI) were 0.49 (0.21–1.82) (human-mouse) and 1.19 (0.22–1.82) (human-rat), well below the 2.0–2.5 Å range for equivalent docking poses. Numbers of interspecies ligand-receptor residue contacts were highly similar, with Sorensen Sc (%) = 96.8 (90.0–100) (human-mouse) and 97.7 (89.5–100) (human-rat). Likewise, numbers of interspecies ligand-receptor residue contacts were highly correlated: Pearson r = 0.913 (human-mouse) and 0.925 (human-rat). Numbers of interspecies ligand-receptor atom contacts were even more tightly correlated: r = 0.979 (human-mouse) and 0.986 (human-rat). Pyramid plots of numbers of ligand-receptor atom contacts by residue exhibited high interspecies symmetry and had Spearman rs = 0.977 (human-mouse) and 0.966 (human-rat). Group B ligands included 15 ring-substituted parabens recently shown experimentally to exhibit decreased binding to human ERα and to exert increased antimicrobial activity. Ligand efficiencies calculated from docking ligands into human ERα-LBD were well correlated with those derived from published experimental data (Pearson partial rp = 0.894 and 0.918; Groups A and B, respectively). Overall, the results indicate that our constructed rodent ERα-LBDs interact with ligands in like manner to the human receptor, thus providing a high level of confidence in extrapolations of rodent to human ligand-receptor interactions.
Breast cancer is the most diagnosed malignancy among women in the United States. Approximately 70% of breast tumors express estrogen receptor alpha and are deemed ER-positive. ER-positive breast tumors depend upon endogenous estrogens to promote ER-mediated cellular proliferation. Decades of research have led to a fundamental understanding of the role ER signaling in this disease and this knowledge has led to significant advancements in the clinical use of antiestrogens for breast cancer treatment. However, adjuvant breast cancer recurrence and metastatic disease progression due to endocrine therapy resistance are prominent and unresolved issues. The established role that estrogens play in breast cancer pathogenesis explains why some patients initially respond to endocrine therapy but also why a significant number of patients become refractory to antiestrogen treatment. It is been hypothesized that exposure to environmental steroid hormone mimics and/or acquired mechanisms of resistance may explain why endocrine therapy fails in a subset of breast cancer patients. This review will highlight: 1) the relationship between ER signaling and breast cancer pathogenesis, 2) the implication of environmental exposures on steroid hormone regulated processes including breast cancer, and 3) the unresolved issue of endocrine therapy resistance.
Two oxidized metabolites of n-butylparaben (BuP) and iso-butylparaben (IsoBuP) discovered in human urine samples exhibit structural similarity to endogenous estrogens. We hypothesized that these metabolites bind to the human estrogen receptor (ER) and promote estrogen signaling. We tested this using models of ER-mediated cellular proliferation. The estrogenic properties of 3-hydroxy n-butyl 4-hydroxybenzoate (3OH) and 2-hydroxy iso-butyl 4-hydroxybenzoate (2OH) were determined using the ER-positive, estrogen-dependent human breast cancer cell lines MCF-7, and T47D. The 3OH metabolite induced cellular proliferation with EC50 of 8.2 µM in MCF-7 cells. The EC50 for 3OH in T47D cells could not be reached. The 2OH metabolite induced proliferation with EC50 of 2.2 µM and 43.0 µM in MCF-7 and T47D cells, respectively. The EC50 for the parental IsoBuP and BuP was 0.30 and 1.2 µM in MCF-7 cells, respectively. The expression of a pro-proliferative, estrogen-inducible gene (GREB1) was induced by these compounds and blocked by co-administration of an ER antagonist (ICI 182, 780), confirming the ER-dependence of these effects. The metabolites promoted significant ER-dependent transcriptional activity of an ERE-luciferase reporter construct at 10 and 20 µM for 2OH and 10 µM for 3OH. Computational docking studies showed that the paraben compounds exhibited the potential for favorable ligand-binding domain interactions with human ERα in a manner similar to known x-ray crystal structures of 17ß-estradiol in complex with ERα. We conclude that the hydroxylated metabolites of BuP and IsoBuP are weak estrogens and should be considered as additional components of potential endocrine disrupting effects upon paraben exposure.
Estrogen receptor alpha gene ( ESR1 ) mutations occur frequently in ER-positive metastatic breast cancer (MBC), and confer clinical resistance to aromatase inhibitors (AIs). Expression of the ESR1 Y537S mutation induced an epithelial-mesenchymal transition (EMT) with cells exhibiting enhanced migration and invasion potential in vitro . When small subpopulations of Y537S ESR1 mutant cells were injected along with WT parental cells, tumor growth was enhanced with mutant cells becoming the predominant population in distant metastases. Y537S mutant primary xenograft tumors were resistant to the antiestrogen tamoxifen (Tam) as well as to estrogen withdrawal. Y537S ESR1 mutant primary tumors metastasized efficiently in the absence of estrogen; however, Tam treatment significantly inhibited metastasis to distant sites. We identified a 9 gene expression signature which predicted clinical outcomes of ER-positive breast cancer patients, as well as breast cancer metastasis to the lung. Androgen receptor (AR) protein levels were increased in mutant models, and the AR agonist dihydrotestosterone (DHT) significantly inhibited estrogen-regulated gene expression, EMT, and distant metastasis in vivo, suggesting that AR may play a role in distant metastatic progression of ESR1 mutant tumors.
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