title: Fludioxonil induced the cancer growth and metastasis via altering epithelial-mesenchymal transition via an estrogen receptor-dependent pathway in cellular and xenografted breast cancer models.
abstract: Fludioxonil is an antifungal agent used in agricultural applications that is present at measurable amounts in fruits and vegetables. In this study, the effects of fludioxonil on cancer cell viability, epithelial-mesenchymal transition (EMT), and metastasis were examined in MCF-7 clonal variant breast cancer cell (MCF-7 CV cells) with estrogen receptors (ERs). MCF-7 CV cells were cultured with 0.1% DMSO (control), 17β-estradiol (E2; 1 ×10-9M, positive control), or fludioxonil (10-5-10-8M). MTT assay revealed that fludioxonil increased MCF-7 CV cell proliferation 1.2 to 1.5 times compared to the control, while E2 markedly increased the cell proliferation by about 3.5 times. When the samples were co-treated with ICI 182,780 (10-8M), an ER antagonist, fludioxonil-induced cell proliferation was reversed to the level of the control. Protein levels of cyclin E1, cyclin D1, Snail, and N-cadherin increased in response to fludioxonil as the reaction to E2, but these increases were not observed when fludioxonil was administered with ICI 182,780. Moreover, the protein level of p21 and E-cadherin decreased in response to treatment with fludioxonil, but remained at the control level when co-treated with ICI 182,780. In xenografted mouse models transplanted with MCF-7 CV cells, fludioxonil significantly increased the tumor mass formation by about 2.5 times as E2 did when compared to vehicle (0.1% DMSO) during the experimental period (80 days). Immunohistochemistry revealed that the protein level of proliferating cell nuclear antigen (PCNA), Snail, and cathepsin D increased in response to fludioxonil as the reaction to E2. These results imply that fludioxonil may have a potential to induce growth or metastatic behaviors of breast cancer by regulation of the expression of cell cycle-, EMT-, and metastasis-related genes via the ER-dependent pathway. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1439-1454, 2017.
authors.affiliation: Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Ryeo-Eun
authors.initials: RE
authors.lastname: Go
authors.affiliation: Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Cho-Won
authors.initials: CW
authors.lastname: Kim
authors.affiliation: Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: So-Ye
authors.initials: SY
authors.lastname: Jeon
authors.affiliation: Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.|Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongwon-gun, Chungbuk, Republic of Korea.
authors.forename: Yong-Sub
authors.initials: YS
authors.lastname: Byun
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Eui-Bae
authors.initials: EB
authors.lastname: Jeung
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Cheongwon-gun, Chungbuk, Republic of Korea.
authors.forename: Ki-Hoan
authors.initials: KH
authors.lastname: Nam
authors.affiliation: Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C513384:CDH1 protein, human; D015820:Cadherins; D004149:Dioxoles; D011758:Pyrroles; D011960:Receptors, Estrogen; D019938:Cyclin D1; C533922:CTSD protein, human; D002402:Cathepsin D; C108339:fludioxonil
keywords: EMT; breast cancer; fludioxonil; metastasis; xenograft models