Biochemical and molecular mechanisms of the preventive action of grape and wine polyphenols against breast cancer

Food components influence the physiology by modulating gene expression and biochemical pathways within the human body. Polyphenolic fruit components such as flavonoids are strong antioxidants and induce the expression of several signal transduction enzymes. The mechanism of selective cytotoxicity induced by red wine polyphenol fraction (RWPF) against MCF-7 breast cancer cells in vitro was investigated in relation to their interference with calcium homeostasis. MCF-7 cells showed an increase in cytosolic calcium levels within 10 minutes of treatment with the polyphenols. RWPF treated MCF-7 cells showed swelling of endoplasmic reticulum, dissolution of the nucleus and loss of plasma membrane integrity as well as reduced mitochondrial membrane potential. These cells were arrested at the G2/M interphase. None of these changes were observed in MCF-10A cells after RWPF treatment. The results suggest that polyphenol-induced calcium release may disrupt mitochondrial function and cause membrane damage resulting in selective cytotoxicity toward MCF-7 cells.; Experiments using athymic nude mice showed that the growth of MCF-7 ER positive xenografts was not significantly inhibited as compared to the controls in response to feeding with grape and wine polyphenol extracts at a concentration of 50mg/kg body weight. Interestingly, MDA-MB231 ER negative xenografts showed significant tumor growth impediment in mice fed with the same concentrations of polyphenol extracts. Results of immunohistochemical studies suggested that polyphenols modulate the estrogen receptor in MCF-7 xenografts. Grape and wine polyphenols appear to prevent MDA-MB231 breast cancer development in vivo independent of the estrogen receptor.; The prostaglandin synthesizing enzyme PTGS2 and enzymes involved in secretion of inflammatory cytokines, the interleukins, were significantly downregulated in MDA-MB231 tumors in addition to cell cycle regulatory genes that encode cyclins and cyclin-dependent kinases. In MCF-7 tumors, the estrogen-responsive genes were upregulated.; Results suggest that dietary regimes including a polyphenol rich diet may offer a promising approach towards breast cancer prevention, possibly ER-ve tumor types, or used in conjunction with conventional prevention therapies where a positive drug-nutrient interaction can be demonstrated.