Increased protein synthesis of IRES containing mRNAs, that induce cell survival and proliferation, by the daidzein metabolite equol may contribute to breast cancer malignancy.

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The effects of soy isoflavones on established breast cancer remain to be understood. We recently reported that dietary daidzein increased primary mammary tumor growth and metastasis, and upregulated eukaryotic protein synthesis initiation factors (eIF) eIF4G and eIF4E. The increased eIF expression in tumor extracts of mice after daidzein diets was associated with protein expression of mRNAs with internal ribosome entry sites (IRES). Results with metastatic cancer cell lines show that the effects of daidzein in vivo can be recapitulated by its metabolite equol. Equol increased metastatic cancer cell viability and up‐regulated gene and protein expression of the transcription factor c‐Myc. In vitro, equol, but not daidzein, up‐regulated eIF4G without affecting eIF4E or its regulator, 4E‐BP, levels. This elevated eIF4G was not associated with eIF4E or 4E‐BP in cap affinity chromatography assays or co‐immunoprecipitations. In dual luciferase assays, IRES‐dependent protein synthesis was increased by equol. As shown by western blotting and polysomal associations, equol specifically increased the expression of IRES‐containing mRNAs of cancer promoting molecules. Therefore, upregulation of eIF4G by equol may result in increased translation of pro‐cancer mRNAs with IRESs and, thus, promote cancer malignancy. Supported by US Army/BCRP W81XWH‐11–1‐0199 to CD and NIH/NIGMS SC3GM084824 to SD.