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




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.

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
1. Overview of naturally occurring endocrine-active substances in the human diet in relation to human health. Nutrition. 2000;16(7-8):654-8. 2. Phytoestrogens and breast cancer. J Steroid Biochem Mol Biol. 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. Dietary phytoestrogens and cancer: in vitro and in vivo studies. J Steroid Biochem Mol Biol. 1992;41(3-8):331-7. 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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