期刊
CARCINOGENESIS
卷 33, 期 5, 页码 1089-1097出版社
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgs110
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- Singapore Biomedical Research Council [BMRC 04/1/21/19/304]
- Singapore National Medical Research Council [R-174-000-137-275]
- US National Institute of Environmental Health Sciences [ES07685]
There is concern that ingestion of dietary phytoestrogens may increase risk of estrogen receptor alpha (ER alpha)-positive breast cancer. The prenylflavone icaritin, a phytoestrogen consumed in East Asian societies for its perceived beneficial effects on bone health, stimulated the growth of breast cancer (MCF-7) cells at low concentrations. Although acting like an estrogenic ligand, icaritin exerted an unexpected suppressive effect on estrogen-stimulated breast cancer cell proliferation and gene expression at higher concentrations. Like estradiol, icaritin could dose-dependently destabilize ER alpha protein. However, destabilization of ER alpha by the estradiol/icaritin combination was profound and greater than that observed for either compound alone. Microarray gene expression analyses implicated aryl hydrocarbon receptor (AhR) signaling for this suppressive effect of icaritin. Indeed, icaritin was an AhR agonist that competitively reduced specific binding of a potent AhR agonist and increased expression of the AhR-regulated gene CYP1A1. When AhR was knocked down by small interfering RNA, the suppressive effect of icaritin on estradiol-stimulated breast cancer cell growth and gene expression was abolished, and ER alpha protein stability was partially restored. Similarly in an athymic nude mouse model, icaritin restricted estradiol-stimulated breast cancer xenograft growth and strongly reduced ER alpha protein levels. Overall, our data support the feasibility for the development of dual agonists like icaritin, which are estrogenic but yet, through activating AhR-signaling, can destabilize ER alpha protein to restrict ER alpha-positive breast cancer cell growth.
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