title: Anti-aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts.
abstract: Targeting the estrogen pathway has been proven effective in the treatment for estrogen receptor positive breast cancer. There are currently two common groups of anti-estrogenic compounds used in the clinic; Selective Estrogen Receptor Modulators (SERMs, e.g. tamoxifen) and Selective Estrogen Enzyme Modulators (SEEMs e.g. letrozole). Among various naturally occurring, biologically active compounds, resveratrol and melatonin have been suggested to act as aromatase inhibitors, which make them potential candidates in hormonal treatment of breast cancer. Here we used a co-culture model in which we previously demonstrated that primary human breast adipose fibroblasts (BAFs) can convert testosterone to estradiol, which subsequently results in estrogen receptor-mediated breast cancer T47D cell proliferation. In the presence of testosterone in this model, we examined the effect of letrozole, resveratrol and melatonin on cell proliferation, estradiol (E2) production and gene expression of CYP19A1, pS2 and Ki-67. Both melatonin and resveratrol were found to be aromatase inhibitors in this co-culture system, albeit at different concentrations. Our co-culture model did not provide any indications that melatonin is also a selective estrogen receptor modulator. In the T47D-BAF co-culture, a melatonin concentration of 20 nM and resveratrol concentration of 20 μM have an aromatase inhibitory effect as potent as 20 nM letrozole, which is a clinically used anti-aromatase drug in breast cancer treatment. The SEEM mechanism of action of especially melatonin clearly offers potential advantages for breast cancer treatment.
authors.affiliation: Division of Environmental Toxicology, Chulabhorn Graduate Institute, Bangkok, Thailand; Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, Thailand; Center of Excellence on Environmental Health, Toxicology and Management of Chemicals, Bangkok, Thailand; Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Thailand. Electronic address: suthat.c@bidi.mail.go.th.
authors.forename: Suthat
authors.initials: S
authors.lastname: Chottanapund
authors.affiliation: Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: M B M
authors.initials: MB
authors.lastname: Van Duursen
authors.affiliation: Division of Environmental Toxicology, Chulabhorn Graduate Institute, Bangkok, Thailand; Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, Thailand; Center of Excellence on Environmental Health, Toxicology and Management of Chemicals, Bangkok, Thailand.
authors.forename: Panida
authors.initials: P
authors.lastname: Navasumrit
authors.affiliation: Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, Thailand.
authors.forename: Potchanee
authors.initials: P
authors.lastname: Hunsonti
authors.affiliation: Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, Thailand.
authors.forename: Supatchaya
authors.initials: S
authors.lastname: Timtavorn
authors.affiliation: Division of Environmental Toxicology, Chulabhorn Graduate Institute, Bangkok, Thailand; Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok, Thailand; Center of Excellence on Environmental Health, Toxicology and Management of Chemicals, Bangkok, Thailand.
authors.forename: Mathuros
authors.initials: M
authors.lastname: Ruchirawat
authors.affiliation: Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Van den Berg
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D001141:Aromatase / Q000235:genetics; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics; D000077289:Letrozole; D008550:Melatonin / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013739:Testosterone / Q000494:pharmacology; D000071163:Trefoil Factor-1; D014230:Triazoles / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D047072:Aromatase Inhibitors; D019394:Ki-67 Antigen; D009570:Nitriles; D013267:Stilbenes; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D014230:Triazoles; D025521:Tumor Suppressor Proteins; D013739:Testosterone; D004958:Estradiol; D000077289:Letrozole; D001141:Aromatase; D008550:Melatonin; D000077185:Resveratrol
keywords: Breast cancer; Co-culture; Human fibroblasts; Melatonin; Resveratrol