Parabens and Human Epidermal Growth Factor Receptor Ligand Cross-Talk in Breast Cancer Cells

Pan, Shawn; Yuan, Chaoshen; Tagmount, Abderrahmane; Rudel, Ruthann A.; Ackerman, Janet M.; Yaswen, Paul; Vulpe, Chris D.; Leitman, Dale C.

doi:10.1289/ehp.1409200

Cited by 51 publications

(30 citation statements)

References 58 publications

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“…These results are in agreement with in vitro data regarding the ability of these compounds to bind to mammalian estrogen receptors and modulate estrogen signaling pathways [3, 5, 28, 47, 53, 125]. Moreover, our detailed comparisons of docking results consistently revealed high similarity between human and rodent ligand-receptor complexes in support of our working hypothesis and indicating that the interspecies sequence differences in these receptors could be regarded as neutral substitutions.…”

Section: Discussionsupporting

confidence: 90%

Homology models of mouse and rat estrogen receptor-α ligand-binding domain created by in silico mutagenesis of a human template: Molecular docking with 17β-estradiol, diethylstilbestrol, and paraben analogs

Gonzalez

Rae

Colacino

et al. 2019

Computational Toxicology

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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.

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Section: Discussionsupporting

confidence: 90%

Homology models of mouse and rat estrogen receptor-α ligand-binding domain created by in silico mutagenesis of a human template: Molecular docking with 17β-estradiol, diethylstilbestrol, and paraben analogs

Gonzalez

Rae

Colacino

et al. 2019

Computational Toxicology

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“…Data in humans have documented parabens in urine in almost all (>96%) of a demographically diverse sample of adults (161), and parabens have been documented in breast cancer specimens. Although the levels were previously thought to be lower than that required to produce estrogenic effects (106), they can stimulate breast cancer cell proliferation in vitro at concentrations 100 times lower when in the presence of the growth factor heregulin (106). A recent study measured urine parabens levels in a diverse sample of 1,151 6-8-year-old girls as a possible determinant of pubertal onset two years later and found no relationship.…”

Section: Wwwannualreviewsorg • Environmental Determinants Of Breastmentioning

confidence: 99%

Environmental Determinants of Breast Cancer

Hiatt

Brody

2024

Annual Review of Public Health

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In the United States, breast cancer is the most common invasive malignancy and the second most common cause of death from cancer in women. Reproductive factors, estrogen, and progesterone have major causal roles, but concerns about other potential causes in the external environment continue to drive research inquiries and stimulate calls for action at the policy level. The environment is defined as anything that is not genetic and includes social, built, and chemical toxicant aspects. This review covers the scope of known and suspected environmental factors that have been associated with breast cancer and illustrates how epidemiology, toxicology, and mechanistic studies work together to create the full picture of environmental effects on this malignancy. Newer approaches to risk-related evaluations may allow this field to move forward and more clearly delineate actionable environmental causes of this most common of cancers in women.

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“…ChIP assay was performed as previously described 39 . U2OS-ERα cells were incubated for 24 hours with 1 μg/ml of doxycycline in serum-free DMEM/F12 upon 80% confluence.…”

Section: Chromatin Immunoprecipitation (Chip)mentioning

confidence: 99%

2’, 3’, 4’-trihydroxychalcone is an Estrogen Receptor Ligand Which Modulates the Activity of 17β-estradiol

Herber

Quirit

Firestone

et al. 2019

Preprint

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Menopausal hormone therapy (MHT) reduces the risk of osteoporosis, fractures, obesity and diabetes, but longterm MHT increases risk of other diseases. Safe long-term MHT that exploits its benefits and abrogates its adverse effects requires a new approach. Here we demonstrate that 2', 3', 4'-trihydroxychalcone (CC7) acts as an estrogen receptor alpha (ERα) ligand that may improve the safety profile of MHT. CC7 reprograms the actions of estradiol (E2) to regulate unique genes in bone-derived U2OS cells, with 824/1358 genes not regulated by E2. The proliferative action of E2 on human MCF-7 breast cancer cells and mouse uterus is blocked when combined with CC7. Thermostability and molecular dynamics simulation studies suggest that CC7 binds concurrently with E2 in the ERα ligand binding pocket to produce a unique coliganded conformation to modulate ERα. Compounds such as CC7 that act as coligands represent a new class of ERα reprograming drugs that potentially can be combined with existing estrogens to produce a safer MHT regimen for long-term therapy. RESULTS CC7 acts as an ER coagonist in U2OS cellsPreviously, we isolated the flavanone liquiritigenin from

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Parabens and Human Epidermal Growth Factor Receptor Ligand Cross-Talk in Breast Cancer Cells

Cited by 51 publications

References 58 publications

Homology models of mouse and rat estrogen receptor-α ligand-binding domain created by in silico mutagenesis of a human template: Molecular docking with 17β-estradiol, diethylstilbestrol, and paraben analogs

Homology models of mouse and rat estrogen receptor-α ligand-binding domain created by in silico mutagenesis of a human template: Molecular docking with 17β-estradiol, diethylstilbestrol, and paraben analogs

Environmental Determinants of Breast Cancer

2’, 3’, 4’-trihydroxychalcone is an Estrogen Receptor Ligand Which Modulates the Activity of 17β-estradiol

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