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Molecular synergy and novel targets of anti-breast cancer phytochemicals
RISK and Prevention, Epidemiology
Background. Epidemiologic studies show that incidence rates of BCa are lowest among Asians. When Asian women moved to developed host countries and adopted their lifestyle and dietary habits, the risk for BCa is significantly increased. These findings suggest that Asian diets contain anti-BCa ingredients. Hypothesis . Attempts to replicate anti-BCa activities of Asian diets using single dietary chemicals have produce equivocal results. We therefore postulate that diet-based protection against BCa is best explained by m olecular synergy and novel targets among dietary phytochemicals, resulting in a broadened chemopreventive index marked by increased distinct anticancer properties and a decreased spectrum of untoward effects that optimally target multiple genetic and epigenetic derangements in BCa. Aims. To simulate anti-BCa protection by Asian diets, we will test combinations of EGCG and resveratrol from tea and grape, with a vitamin g -tocotrienol, as a cocktail for evaluation in normal, ER (+ve) and ER (-ve) BCa cells (aim #1). This strategy arguably better resembles Asian diets than single agents. Once an optimally active cocktail is discovered, w e will proceed to identify cellular targets that mediate their bioactivities (aim #2). We will use an affinity proteomics strategy already validated for resveratrol and applicable also to EGCG and g -tocotrienol as revealed in pilot experiments. Biological significance of identified targeting proteins for each chemical and their combination will be validated using archived pathological specimens and their matched normal counterparts (aim #3). Design. We will first determine a sub-optimal and optimal dose for each agent. We will test all 8 possible sub-optimal and optimal dose combinations to ascertain whether synergy exists. We will empirically select the best combination for further proteomics analysis. Target proteins revealed by proteomics will be analyzed using archived tissues. Research Benefits. As the second leading cause of cancer death in women, diet-based prevention and treatment of BCa provides an easily compliant and economical healthcare alternative. The cocktail approach we propose will shed insights on benefits of Asian diets, and also can be correlated with specific targeting proteins of BCa. Together, our findings should constitute reasonable evidence and mechanistic frameworks to further investigate efficacy of this dietary combination in animal models and clinical studies.
Breast cancer (BCa) is a significant cause of death in American women. Hormonal therapies and surgery both provide relief. However, treatment options are lacking when the disease relapses at local or distant sites. Choices are also limited for BCa without estrogen receptors since they are resistant to hormonal therapies but occur in 30% of primary BCa and also frequently in recurrent BCa. A sian females have lower BCa risk, as inverse correlates of foods rich in phytochemicals. Asian women who immigrated to America have BCa risks comparable to Caucasian females, suggesting that dietary protection against BCa has been lost. The manner by which Asian diets exert their BCa-protective effect remains to be completely elucidated. We hypothesize that traditional Asian diets contain anti-BCa phytochemicals in combination. We propose to develop an anti-BCa cocktail using EGCG and resveratrol from tea and grape, with vitamin E derivative, g- tocotrienol . These agents are likely found in abundance in Asian diets. We hypothesize that these agents in combination, exert molecular synergy in affecting BCa growth and gene expression. We will first test whether the combination of EGCG, resveratrol and g -tocotrienol is significantly more effective in reducing growth, inducing programmed cell death, and suppressing the expression of a breast cancer growth protein named cyclin D1 , than the individual components. These experiments will use normal breast cells, for comparison with female hormone-dependent and –resistant BCa cells. A second objective is to explore the hypothesis that each bioactive agent selected - EGCG, resveratrol, g -tocotrienol – is capable of binding and interacting with specific cellular protein targets, which may explain why these agents combined are more active in inhibiting cell proliferation, affecting programmed cell death, and suppressing the expression of cyclin D1. Finally, our goal is to validate results obtained in breast cancer culture cells with archived breast cancer/matched non-malignant specimens, with respect to qualitative and quantitative differences in those targets revealed by culture studies. Our proposed studies should provide insights on how Asian diets might exert protection again BCa in women, and lay the foundations for further detailed investigation of this nutrient combination in animal models and clinical interventions in the future .