| [Background]Basic research suggests that estrogen plays a key role in the etiology of breast cancer. Its metabolites, particularly catechol estrogen, are involved in the carcinogenesis as well. Specifically, estrogen can induce more cell proliferation via estrogen receptor mediated cellular event, while catechol estrogen may cause reactive oxygen species which have the potential to result in permanent nucleotide mutation. Both of these two mechanisms may lead to breast cancer.Migration studies indicated the importance of changing lifestyle in the etiology of breast cancer and implied that western lifestyle may be a risk factor for breast cancer. Compared with its western counterpart, East Asian women eat more soy food, green tea, allium vegetables and fruits. These foods possess high concentrations of polyphenols, particularly isoflavanol, flavanols and flavonols.With similar structure to but a great extent lower bioactivity, Isoflavones may compete with estrogen, hence the potential to decrease the function of estrogen. However, growing evidence indicates that soy consumption alone is unlikely to explain the low rates of breast cancer in East Asian. Therefore, we focused the 2nd pathway of estrogen metabolites induced breast cancer. Like isoflavonols, flavanols and flavonols have similar structure but low bioactivity with catechol estrogen. It should have some anti-carcinogen functions. Besides, they possess some other functions related to cancer prevention including the inhibition of phaseⅡdetoxifying enzymes property. Company with other phaseⅡenzymes, GST involves in the detoxifying process of estrogen metabolizes. Basic research suggests polyphenols can inhibit phaseⅡenzyme, like GST. However, research on the ingredient of polyphenols and GST indicated that the actual relationship between polyphenols and GST varies. EGCG/EGC can induce GST, Kaempferol and Quercetin inhibit GSTM, while EC has no effect on GST.Plenty of in vitro studies implied that polyphenols possess anti carcinogenic functions. Bioavailability is essential to its potential effect in vivo. The preparation of food may lead to substantial loss of polyphenols, since they usually exist on the outer section of food. Further, bioavailability is influenced by absorption, metabolism and inter-person variation. Thus, urinary excretion of polyphenols may be a more accurate measure of bioavailability than a food frequency questionnaire. Urinary excretion of polyphenols reflects recent intake levels of polyphenols. However, it may be reasonable to regard that personal dietary preference is relatively stable over time.[Primary hypotheses]1) urinary polyphenols, particularly flavonols and flavanols reduce breast cancer risk;2) genetic polymorphisms in genes involved in the metabolism of reactive oxygen species (ROS) are related to the risk of breast cancer;3) the inverse association between antioxidants, particularly polyphenols, and breast cancer risk is more pronounced among women with genotypes that favor the formation of ROS[Subjects and Methods]Shanghai Women's Health Study (SWHS) is a population based cohort study with more than 70 thousand subjects with high participation rate and high rates of follow up. 87.7% donate urine sample before diagnosis. Almost the same amount of subjects donate DNA samples. In our nested case control study,436 cases were individually matched with 852 controls by age at baseline (±2 years), date at study enrollment (≤30 days), time (morning or afternoon) of urine collection, interval since last meal (≤2 hours), menopausal status (pre- or post-), and antibiotic use (yes/no) in the past week. In total,352 cases and 701 controls were available for this study.Urinary polyphenols were determined by liquid chromatography electrospray mass spectrometry (LC/ESI-MS). Real-time multiplex PCR were used for GSTM and GSTT genetyping. ORs were estimated using conditional logistic regression. Restricted cubic spline was estimated using R package.[Results]Urinary excretion of tea polyphenols increased with increasing tea leaves consumption among controls, but not breast cancer cases. Compared with cases, controls had higher levels of urinary polyphenols, particularly epicatechin. In contrast, we did not find any dose-response relationship between urinary polyphenols and breast cancer. Urinary excretion of epicatechin was inversely associated with breast cancer risk [Odds Ratio=0.59 (95% CI:0.39-0.88) for the intermediate tertile versus the lowest tertile], although risk was not reduced for highest tertile level. In spline curve, we found an overall dose-response relationship between level of epicatechin and breast cancer risk.Among those with GSTM1 null genotype, increased urinary excretion of EGC was associated with a reduced risk of breast cancer, with ORs (95% CI) of 0.66 (0.41-1.05) and 0.64 (0.41-1.01) for the middle and highest tertile of excretion levels, respectively, compared to women in the lowest tertile of EGC (p for trend,0.058). Conversely, among women with one or two copies of GSTM1, EGC was positively associated with the risk of breast cancer (p for trend,0.10). Similarly, urinary excretion of flavonols, particularly kaempferol, also was associated with an increased risk of breast cancer among those with at least one copy of GSTM1.Further, we found that urinary excretion of flavonols (p for interaction,0.03) and flavonols (p for interaction,0.03), particularly EGC (p for interaction, P<0.01), significantly interacted with joint genotypes of GSTM1 and GSTT1 in relation to breast cancer. Among women null for both GSTM1 and GSTT1, breast cancer risk decreased with increasing levels of flavanols (p for trend,0.09) and flavonols (p for trend,0.03), with OR of 0.57 (0.30-1.09) and 0.49 (0.25-0.93) among those in the highest tertile of flavanols and flavonols, respectively. Conversely, among those with at least one copy for both GSTM1 and GSTT1, breast cancer risk rose with increasing levels of urinary flavonols, primarily kaempferol (p for trend,0.04). Breast cancer risk for women in the highest tertile of kaempferol have more than doubled (OR=2.41 (1.04-5.59)) than that for women in the lowest tertile.We calculated the ROC and AUC for subjects drinked tea more than 1.5 liang, 2.5 liang and 4.0 liang per month respectively. It was obvious EGC and GST polymorphism could achieve almost the same level of AUC among all those 3 subsets as Gail model. After adding EGC and GST to Gail model, the AUC increased obviously. For subjects drink tea more than 4 liang/month, the AUC elevated from 0.66 to 0.77 for Gail model added EGC and GSTT (p=0.06). The same scenario was also happened for Gail model added the ratio of EGC to tea consumption and GSTT.[Conclusions]Breast cancer patients and normal subjects may have different models on metabolizing flavanols and flavonols which poccess similar structure with estrogen metabolites. Urinary excretions of flavanols and flavonols increase with increasing amount of green tea intakes, but no such dose response relationship is found in breast cancer patients.Compared with normal controls, urianry excretions of falvanols and flavonols are lower in breast cancer patients. However, we did not find any dose-response relationship between urinary polyphenols and breast cancer.The association between urianry excretions of falvanols and flavonols with breast cancer are modified by GST(GSTM1 and GSTT1). The inverse association between EGC and breast cancer is more significant among subjects with lower GST. While falvonols, particularly kaempferol may increase the risk of breast cancer among subjects with higher GST.Adding EGC and GST to Gail model which includes age of menarche, age of first live birth and breast cancer history in first degree relatives increase the discriminative properties of Gail model. If it is confirmed in further studies, it may be used to assess the risk of breast cancer.
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