Genetic modulation of the vitamin d intake and postmenopausal breast cancer risk
The effect of phytoestrogens on postmenopausal breast cancer risk and possible anticarcinogenic mechanisms Supervisor: Collaboration:
Phytoestrogens are plant-derived organic nonsteriodal compounds that are able to bind to mammalian estrogen receptors. Isoflavones and lignans are two principal groups of dietary phytoestrogens, which have shown antiestrogenic, antioxidant and antiinflammatroy effects (1). Epidemiologic evidence has linked high phytoestrogen consumption, particularly soy consumption, in Asian populations to lower risk of breast cancer compared to Western populations. Studies of phytoestrogen intake and/or metabolites of isoflavone (equol) and lignan (enterolactone) in Western populations have demonstrated although not consistently a protective effect for breast cancer and this inconsistency may be partly explained by the choice of markers used (2). Recently, an increased risk associated with serum isoflavone levels, but not lignan levels, was even reported in a small prospective study (3). Lignans are the main class of phytoestrogens in Western diets and may thus play a more important role. There is need for clarification of a potential differential effect by menopausal status and estrogen receptor status (4,5). Urinary phytoestrogens correlated positively with plasma sex hormone binding globulin (SHBG) in cross-sectional studies (6). Dietary intervention involving increased phytoestrogen intake has indeed been shown to decrease plasma testosterone and estradiol levels and increase SHBG levels) among postmenopausal women with high plasma testosterone levels (7). There is also some evidence that phytoestrogens may directly modulate concentrations of circulating estradiol by inhibiting enzymes involved in estrogen biosynthesis and metabolism, such as 17ß-hydroxsteriod oxidoreductase, aromatase, and steroid sulfatase (8,9,10). A strong association between dietary isoflavones and plasma estradiol was recently observed only in women carrying the CC genotype for ESR1 PvuII (11). The relationship between phytoestrogens and breast cancer risk may therefore be modified by genetic variants involved in estrogen metabolism. The further clarification of the role of phytoestrogens on postmenopausal breast cancer risk regarding type of dietary phytoestrogens, possible mechanisms and diet-gene interactions would provide valuable information for dietary recommendations and intervention programmes to prevent breast cancer. Aims
The objective of the project is to quantify the association of phytoestrogen intake with postmenopausal breast cancer risk, genetic variants in candidate genes and the risk for. Specific aims are: (i) to evaluate and quantify the association between different classes of phytoestrogens and breast cancer risk, (ii) to evaluate and quantify the association between serum levels of isoflavone and lignan metabolites (equol and enterolactone) and breast cancer risk, (iii) to assess the correlation of phytoestrogens exposure with plasma estradiol and SHBG, and (iv) to assess the effects of relevant genetic variants on the association between phytoestrogens and breast cancer risk. Study plan
The proposed study questions will be investigated in MARIE, a population-based case- control study of postmenopausal breast cancer, including ca. 3500 cases and 7000 age- matched controls recruited by the end of 2005 in two study regions, Rhein-Neckar- Karlsruhe and Hamburg. Detailed information on all relevant risk factors for breast
cancer was obtained through personal interviews conducted by trained interviewers using a standardised study questionnaire. Dietary information was collected through a validated 176-item self-administered nutritional questionnaire used in the European Prospective Investigation into Nutrition and Cancer and the data will be available for this project. Clinical data was collected from patient records. Aliquots of serum and EDTA-blood samples are available from the patients and stored at - 80°C and DNA will be extracted. In the project phase, the dietary phytoestrogen intake will be estimated from the dietary data based on an updated database of phytoestrogen-containing foods previously established using the available analytical data from the literature (5). Never thawed serum sample aliquots of 600 selected healthy subjects stratified by use of hormone replacement therapy at the time of blood sampling will be analysed for enterolactone and equol using time-resolved fluoro-immunoassay (TR-FIA). Plasma 17ß-estradiol and SHBG will be performed using radioimmunoassay after ether extraction. Quality control measures will be included. Genotype data relevant for this project will be available from other planned projects. The association between dietary phytoestrogens, serum phytoestrogen and plasma hormone concentrations will be described using multiple regression to control for age and BMI. Kruskal-Wallis test will be used to compare differences in dietary and serum phytoestrogen concentrations among subjects with different genotypes. ANOVA will be used to compare differences in plasma estradiol and SHBG concentrations. The association between dietary phytoestrogens and serum metabolites (separately for isoflavone and lignan) and breast cancer risk will be assessed using logistic regression analysis for adjustment of possible confounders in all subjects as well as among subjects with different genotypes. First order interactions between phytoestrogens (dietary and serum levels) and genotypes of the individual polymorphisms will be estimated under the standard multiplicative model.
Preliminary title of the dissertation Mechanisms and genetic modulation of the association between phytoestrogen intake and postmenopausal breast cancer risk References
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Phytoestrogen concentrations in serum and spot urine as biomarkers for dietary phytoestrogen intake and their relation to breast cancer risk in European prospective investigation of cancer and nutrition-norfolk. Cancer Epidemiol Biomarkers Prev. 2004;13(5):698-708.
lignan intakes and risk of pre- and postmenopausal breast cancer. Int J Cancer. 2004;111(3):440-3.
Dietary phytoestrogen intake and premenopausal breast cancer risk in a German case-control study. Int J Cancer. 2004;110(2):284-90.
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le sex hormones through a comprehensive change in diet: the diet and androgens (DIANA) randomized trial. Cancer Epidemiol Biomarkers Prev. 2001;10(1):25-33.
quol excretion in relation to 2-hydroxyestrone
and 16alpha-hydroxyestrone concentrations: an observational study of young to middle-aged women. J Steroid Biochem Mol Biol. 2003;86(1):71-7.
inhibit aromatase enzyme in human preadipocytes. J Steroid Biochem Mol Biol. 1994;50(3-4):205-12.
Phytoestrogens are potent inhibitors of estrogen sulfation: implications for breast cancer risk and treatment. J Clin Endocrinol Metab. 2004;89(4):1779-87.
Phytoestrogen exposure correlation with plasma estradiol in postmenopausal women in European Prospective Investigation of Cancer and Nutrition-Norfolk may involve diet-gene interactions.Cancer Epidemiol Biomarkers Prev. 2005;14(1):213-20.
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