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 ×10-9 M, positive control), or
fludioxonil (10-5 -10-8 M). 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 (10-8 M), 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.