title: Hormonally active doses of isoflavone aglycones promote mammary and endometrial carcinogenesis and alter the molecular tumor environment in Donryu rats.
abstract: Our research is focused on modifying effects of an isoflavone aglycones (IAs)-rich extract at a hormonally active dose of 150 mg/kg body weight/day on mammary and endometrial carcinogenesis in female Donryu rats. IA administered for 2 weeks in a phytoestrogen-low diet exerted estrogenic activity and induced cell proliferation in the uterus of ovariectomized rats. Furthermore, administration for 4 weeks resulted in elevation of cell proliferation in the mammary glands of 7,12-dimethylbenz[a]anthracene (DMBA)-treated animals. Forty weeks of postpubertal administration of IA to 5-week-old rats after initiation of mammary and endometrial carcinogenesis with DMBA and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) caused significant increase of incidence and multiplicity of mammary adenocarcinoma, multiplicities of endometrial atypical hyperplasia, adenomatous polyps, and an increased trend of uterine adenocarcinomas. Liquid chromatography with tandem mass spectrometry and immunohistochemical analyses revealed significant elevation of tumorigenesis-related proteins such as S100 calcium-binding protein A8, kininogen 1, and annexins 1 and 2 in mammary adenocarcinomas and cadherin EGF LAG seven-pass G-type receptor 2, DEAD box polypeptide 1, and cysteine- and glycine-rich protein 1 in uterine proliferative lesions of IA-treated animals. Those changes are likely to be related to modulation of estrogen receptor (ER), AP1, nuclear factor-kappa B, and actin signaling pathways. Our results indicate that the postpubertal exposure of Donryu rats to IA at an estrogenic dose results in promotion of mammary and uterine carcinogenesis induced by DMBA and ENNG, which might be related to the activation of ER-dependent signaling and alteration of the molecular tumor environment in the mammary gland and endometrium.
authors.affiliation: Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Anna
authors.initials: A
authors.lastname: Kakehashi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tago
authors.forename: Midori
authors.initials: M
authors.lastname: Yoshida
authors.forename: Yui
authors.initials: Y
authors.lastname: Sokuza
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukushima
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000375:Aging; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003043:Cocarcinogenesis; D019587:Dietary Supplements / Q000009:adverse effects; D016889:Endometrial Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D007529:Isoflavones / Q000008:administration & dosage* / Q000009:adverse effects; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D010052:Ovariectomy; D048789:Phytoestrogens / Q000008:administration & dosage* / Q000009:adverse effects; D010936:Plant Extracts / Q000009:adverse effects; D051381:Rats; D011919:Rats, Inbred Strains; D047368:Tumor Burden / Q000187:drug effects; D014599:Uterus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D007529:Isoflavones; D009363:Neoplasm Proteins; D048789:Phytoestrogens; D010936:Plant Extracts