The nuclear signaling pathways by which resveratrol is involved have been mapped in considerable detail. Interestingly, many of the points of influence are also targets for curcumin (the spice turmeric), and epigallocatechin gallate (EGCG), a constituent of green tea. This would explain the similar epidemiologic patterns of tea and wine consumption as they relate to cancer.
Wine consumption has also been reported to be associated with less severe fibrosis from radiation treatment in women with breast cancer. As an added benefit, evidence indicates that resveratrol and other wine components help to sensitize tumor cells to radiation while protecting normal cells. A similar paradox applies to chemotherapy, at least in tissue culture and animal studies. This was dramatically demonstrated with doxorubicin and cisplatin in human gynecologic cancer cell lines and in isolated rat hearts.16 If confirmed in clinical trials, these would be very exciting findings but level 1 evidence has not been published so caution is in order.
Wine, Resveratrol, and Breast Cancer: Special Considerations
One of the first cell lines to be proven sensitive to resveratrol is breast cancer, and the effect applies regardless of ER status. However, the relationship of wine consumption and breast cancer has been problematically reported, causing confusion as to whether resveratrol is useful or even safe for breast cancer patients, and whether wine consumption has the same risk as alcohol. Several meta-analyses have been done on the subject of alcohol and breast cancer, with a linear dose-response correlation generally observed. More recent studies employ mathematical modeling to account for the well-known self-reporting bias on drinking levels, but the effect of moderate consumption remains at least in part a matter of extrapolation. Given the anti-cancer activity of resveratrol and other wine phenolics in vitro, the question of whether wine drinkers obtain any benefit in terms of relative cancer risk has been of intense interest.
Conflicting results from the various studies that have attempted to stratify results for different types of alcohol consumed has led to even greater confusion. A 2010 study from the Fred Hutchinson Cancer Research Center in Seattle concluded that there was “no difference between red wine or white wine consumption and breast cancer risk” while a 2009 report from Kaiser-Permanente found “red wine carries the same risk of breast cancer as white wine.” These authors went on to state that “women who consume any type of alcohol are at greater risk for breast cancer” and there is “no difference between types of drinks.” Earlier studies suggested that as little as 1.5 glasses of wine a day was enough to double lifetime risk of breast cancer.
Yet closer reading of the Fred Hutchinson Center study reveals that “Wine consumption was not associated with risk of breast cancer and no differential was observed between red and white wine.” The reason for the lack of difference in risk was that there was no increased risk in the wine drinking cohort for either type. About the same time as the Kaiser-Permanente results were being presented, a new meta-analysis from Japan was published that concluded that “epidemiologic evidence on the association between alcohol drinking and breast cancer risk remains insufficient” despite the dozens of studies available for review.
Studies from European populations, meanwhile, give a different picture. A 2008 report from the University of Montpelier in France found that “women who consumed at least a glass of wine a day had about 50% less breast cancer than nondrinkers.”17 Contradictory results such as these can best be explained by differences in the study populations rather than as statistical outliers. In order to know the true effect of wine consumption, and by inference wine’s constituent polyphenols, a study population must have a consistent drinking pattern; for example one glass of red wine daily, with dinner, rarely in excess, and generally not overlapping with other types of alcoholic beverages. Traditional lifestyles in southern France fit this description, while American and other populations have a more mixed drinking pattern. In contrast to the Mediterranean lifestyle, the woman who consumes a glass or two of red wine on a daily basis and nothing else is uncommon, despite indicating a preference for wine in survey responses. On balance then, consideration should be given to giving greater weight to the European data.
What does this mean to the woman concerned about alcohol and breast cancer risk? A case could certainly be made for allowing a glass or two of red wine without concern about added risk, and perhaps even some benefit in terms of reduced risk applies. Resveratrol is however an ER agonist, so supplementing resveratrol in place of a healthy drinking habit may have greater risks for certain types of breast cancer. This remains to be clarified.
Resveratrol as a Phytoestrogen
A dose-dependent relationship exists between wine consumption and bone density. Given the significant morbidity from osteoporosis with age, this translates to a benefit in terms of both quality of life and mortality. Here again resveratrol provides a plausible cause-effect relationship, as an ER agonist with high degree of affinity.18 Hormone replacement therapy for post-menopausal women remains highly controversial, so phytoestrogens may provide an alternative if they can be proven selective and effective.
Estrogen receptors exist in many tissues throughout the body, including brain, kidney, heart, vascular endothelium, prostate, and bone, in addition to breast, ovary, and endometrium. They are broadly divided into 2 types, though many isoforms exist within each category, and receptor binding produces different effects from different agonists. For example, tamoxifen is an ER antagonist in breast tissue but an agonist in bone and endometrium. Furthermore, any given molecule may act as both a transcriptional co-activator and co-repressor within the same tissue, depending on dose and homeostatic compensation. This results in a considerable challenge in identifying all of the actions of a given ER modulator, and the various effects of phytoestrogens are incompletely known.
Resveratrol has been shown to be an ER agonist in vascular endothelium, and release of the vasodilator NO may be driven by this interaction. This may mimic the role of endogenous estrogen in protecting against atherosclerosis. Resveratrol also stimulates ER’s in bone, resulting in up-regulation of bone morphogenic proteins. A more complex picture characterizes the interactions of resveratrol and ER’s in breast tissue. Though it has a strong binding affinity, there is evidence that resveratrol may block the formation of estrogen-DNA adducts and estrogen-induced cell transformation at multiple sites, independent of its other anti-tumor actions. Additionally, resveratrol appears to reverse the epigenetic silencing of BRCA-1, a tumor suppressor involved in DNA repair, which is down-regulated in some types of breast cancer. This effect is mediated via the aromatic hydrocarbon receptor (AhR), in parallel with reduced occupancy of the alpha type ER. On balance then, the role of resveratrol appears protective but not thoroughly understood.
Figure 3. Diethylstilbestrol
A cursory look at ER agonists reveals a common ligand shared by resveratrol and other phytoestrogens. Among the most similar to resveratrol is the synthetic estrogen diethylstilbestrol, or DES. This was widely prescribed for estrogen replacement in the mid-twentieth century, and eventually withdrawn from the market when it was found to be associated with clear cell vaginal and cervical adenocarcinoma in adult offspring of women who were took it during pregnancy. Additionally, the mothers were found to be at increased risk for breast cancer. Given the several decades that it took to discover these problems, caution must be observed with the use of similar compounds especially for pregnant women. The use of phytoestrogens in men has not been well studied and should also be viewed with prudence.
Resveratrol and Telomerase
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