a1 INRA, UMR 1019, Unité Nutrition Humaine, Centre Clermont-Theix, F-63122 St Genès Champanelle, France
a2 Laboratoire d'Oncologie Moléculaire, UMR 484 INSERM-UdA, Centre Jean Perrin, F-63011 Clermont-Ferrand, France
Epidemiological evidence together with preclinical data from animal and in vitro studies strongly support a correlation between soy isoflavone consumption and protection towards breast and prostate cancers. The biological processes modulated by isoflavones, and especially by genistein, have been extensively studied, yet without leading to a clear understanding of the cellular and molecular mechanisms of action involved. This review discusses the existing gaps in our knowledge and evaluates the potential of the new nutrigenomic approaches to improve the study of the molecular effects of isoflavones. Several issues need to be taken into account for the proper interpretation of the results already published for isoflavones. Too often knowledge on isoflavone bioavailability is not taken into account; supra-physiological doses are frequently used. Characterization of the individual variability as defined by the gut microflora composition and gene polymorphisms may also help to explain the discrepancies observed so far in the clinical studies. Finally, the complex inter-relations existing between tissues and cell types as well as cross-talks between metabolic and signalling pathways have been insufficiently considered. By appraising critically the abundant literature with these considerations in mind, the mechanisms of action that are the more likely to play a role in the preventive effects of isoflavones towards breast and prostate cancers are reviewed. Furthermore, the new perspectives opened by the use of genetic, transcriptomic, proteomic and metabolomic approaches are highlighted.
Abbreviations: AF, activation functions; AP-1, activator protein 1; AR, androgen receptor; CDK, cyclin-dependent kinase; COMT, catechol-O-methyltransferase; CYP, cytochrome P450 monooxygenase; Da, daidzein; DHEA, dihydroepiandrosterone; DHT, dihydrotestosterone; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; Eq, equol; ER, estrogen receptor; ERE, estrogen responsive elements; ERK, extracellular signal-regulated kinase 1; FSH, follicel-stimulating hormone; Ge, genistein; GPx, glutathione peroxidase; GSR, glutathione reductase; GST, glutathione S-transferase; GTP-CH1, GTP cyclohydrolase 1; IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor 1 receptor; IGFBP, insulin-like growth factor binding protein; JNK, c-jun N-terminal kinase; LDL, low density lipoprotein; LH, luteinising hormone; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; MS, mass spectrometry; MT-1X, metallothionein 1X; mGST, microsomal glutathione S-transferase; NF-κB, nuclear factor-kappa B; NMR, nuclear magnetic resonance; PI3K, phosphatidylinositol-3 kinase; PIN, prostatic intra-epithelial neoplasia; PPAR, peroxisome proliferator-activated receptor; PR, progesterone receptor; PSA, prostate specific antigen; QR, quinone reductase; SD rats, Sprague–Dawley rats; SHBG, sex hormone binding globulin; SNPs, single nucleotide polymorphisms; SOD, superoxide dismutase; TEBs, terminal end buds; TGF-β, transforming growth factor β; TIMP, tissue inhibitor of metalloproteinase; TRAMP, transgenic adenocarcinoma of the mouse prostate; UDPGT, UDP-glucuronosyl-transferase; VEGFR, vascular endothelial growth factor receptor