Bisphenol AF as an Inducer of Estrogen Receptor β (ERβ): Evidence for Anti-estrogenic Effects at Higher Concentrations in Human Breast Cancer Cells.

Abstract

Bisphenols are endocrine disruptors that are widely found in the environment. Accumulating experimental evidence suggests an adverse interaction between bisphenols and estrogen signaling. Most studies have performed experiments that focused on estrogen receptor (ER) engagement by bisphenols. Therefore, the effects of bisphenols on the expression of ERα (ESR1) and ERβ (ESR2) remain largely unknown. In the present study, we examined the effects of four bisphenols: bisphenol A (BPA), bisphenol B (BPB), bisphenol S (BPS), and bisphenol AF (BPAF), on estrogen signaling in two human breast cancer cell lines (MCF-7 and SK-BR-3). Among these bisphenols, BPAF up-regulated the expression of ERβ, and this was coupled with the abrogation of estrogen response element (ERE)-mediated transcriptional activities as well as the down-regulation of Cdc2 expression in MCF-7 cells, without influencing the expression of ERα. BPAF functioned as an agonist of ERα at lower concentrations (nanomolar order), but did not exhibit any modulatory action on ERα transiently expressed in SK-BR-3 cells in the presence or absence of 17β-estradiol (E2) at higher concentrations (micromolar order). The introduction of ERβ cDNA resulted in greater reductions in MCF-7 cell viability than with BPAF alone. Since ERβ is a suppressive molecule of ERα function, these results provide rational evidence for BPAF functioning as an anti-estrogenic compound via the induction of ERβ at higher concentrations.

• Authors: Hiroyuki Okazaki, Shuso Takeda, Kazuhiro Kakizoe, Aya Taniguchi, Miki Tokuyasu, Taichi Himeno, Hiroyuki Ishii, Eriko Kohro-Ikeda, Koichi Haraguchi, Kazuhito Watanabe, Hironori Aramaki
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 40 Issue 11 Pg. 1909-1916 ( 2017) ISSN: 1347-5215 [Electronic] Japan
• PMID: 29093337 (Publication Type: Journal Article)

Chemical References

• Benzhydryl Compounds
• ESR1 protein, human
• ESR2 protein, human
• Endocrine Disruptors
• Estrogen Antagonists
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Estrogens
• Phenols
• Estradiol
• CDC2 Protein Kinase
• CDK1 protein, human
• 4,4'-hexafluorisopropylidene diphenol

Topics

• Benzhydryl Compounds (pharmacology)
• CDC2 Protein Kinase (metabolism)
• Dose-Response Relationship, Drug
• Down-Regulation
• Endocrine Disruptors (pharmacology)
• Estradiol (metabolism)
• Estrogen Antagonists (pharmacology)
• Estrogen Receptor alpha (agonists, metabolism)
• Estrogen Receptor beta (metabolism)
• Estrogens (metabolism)
• Female
• Humans
• MCF-7 Cells
• Phenols (pharmacology)
• Response Elements (drug effects)
• Signal Transduction (drug effects)
• Transcription, Genetic (drug effects)
• Up-Regulation