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Role of Protein Synthesis Initiation Factors in Dietary Soy Isoflavone-Mediated Effects on Breast Cancer Progression
Annual summary 1 Mar 2012-28 Feb 2013
PUERTO RICO UNIV SAN JUAN SCHOOL OF MEDICINE
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The beneficial effects of soy on established breast cancer is controversial. The goal of this research is to investigate the potential molecular mechanisms by which soy isoflavones affect established breast cancers. A recent study by our laboratory reported that dietary genistein reduced tumor growth and metastasis and down regulated cancer promoting genes in a nude mouse model with tumors established from MDA-MB-435 metastatic cancer cells. In contrast, daidzein increased primary mammary tumor growth and metastasis, and significantly upregulated genes that regulate proliferation and protein synthesis including eukaryotic initiation factor eIF4F members eIF4G1 and eIF4E. The purpose of this study is to investigate the molecular mechanisms by which soy isoflavones genistein and daidzein disparately regulate protein synthesis initiation in established breast cancer. Our hypothesis is that soy isoflavones modulate breast cancer progression by specific regulation of the eIF4F eukaryotic initiation factor complex to affect the synthesis of cancer regulatory proteins. Using MDA-MB- 435 metastatic cancer cell lines, we recently reported de la Parra, et al, 2012, J. Biol. Chem.,that the metabolite of daidzein, equol, upregulated eIF4G and c- Myc, and specifically increased the protein expression of IRES containing cell survival and proliferation-promoting molecules. The 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. Polysomal associations demonstrated that equol specifically increased protein synthesis and the association of IREScontaining mRNAs of cancer promoting molecules. To validate a role for elevated eIF4G in the cellular responses to equol, eIF4G expression was knocked down using specific shRNA.
APPROVED FOR PUBLIC RELEASE