Dataset Information

Interaction of soy and 17beta-HSD1 gene polymorphisms in the risk of endometrial cancer.

ABSTRACT: In-vitro studies have found that soy isoflavones can inhibit the activity of 17beta-hydroxysteroid dehydrogenase type I, a key enzyme in catalyzing estrone (E1), to the biologically more active estradiol (E2).We hypothesized that soy food consumption may interact with polymorphisms in the 17beta-HSD1 gene in the development of endometrial cancer and evaluated this hypothesis in the Shanghai Endometrial Cancer Study.Shanghai Endometrial Cancer Study is a population-based case-control study conducted among Chinese women in Shanghai. This study consisted of 1204 incident endometrial cancer cases diagnosed between 30 and 69 years of age and 1212 age frequency-matched community controls recruited from 1997 to 2003. Overall participation rates were 82.8% for cases and 74.4% for controls, whereas the DNA collection rates were 95.1% for cases and 94.2% for controls.We found that women carrying at least one A allele of the rs605059 polymorphism had a significant 18% reduction in risk of endometrial cancer compared with those without an A allele, and the association was primarily restricted to premenopausal women. The odds ratio (95% confidence interval) was 0.65 (0.47-0.88) for premenopausal women with at least one A allele versus those without an A allele. We also found that among premenopausal women soy isoflavone intake significantly interacted with the rs605059 genotype in relation to endometrial cancer and that the inverse association between soy isoflavone intake and endometrial cancer only appeared among those with at least one A allele of the rs605059 polymorphism. Among postmenopausal women, the association of soy isoflavone intake with endometrial cancer did not differ by 17beta-HSD1 genotypes. We did not find that the rs2676530 polymorphism was significantly associated with endometrial cancer risk.Our results suggest that soy consumption may interact with polymorphisms in the 17beta-HSD1 gene in relation to endometrial cancer risk. Further studies are warranted to confirm our results.

SUBMITTER: Dai Q

PROVIDER: S-EPMC2238679 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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Interaction of soy and 17beta-HSD1 gene polymorphisms in the risk of endometrial cancer.

Dai Qi Q Xu Wang-Hong WH Long Ji-Rong JR Courtney Regina R Xiang Yong-Bing YB Cai Qiuyin Q Cheng Jiarong J Zheng Wei W Shu Xiao-Ou XO

Pharmacogenetics and genomics 20070201 2

<h4>Background</h4>In-vitro studies have found that soy isoflavones can inhibit the activity of 17beta-hydroxysteroid dehydrogenase type I, a key enzyme in catalyzing estrone (E1), to the biologically more active estradiol (E2).<h4>Objective</h4>We hypothesized that soy food consumption may interact with polymorphisms in the 17beta-HSD1 gene in the development of endometrial cancer and evaluated this hypothesis in the Shanghai Endometrial Cancer Study.<h4>Methods</h4>Shanghai Endometrial Cancer ...[more]

PMID: 17301695

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Project description:BACKGROUND: Bisubstrate enzymes, such as 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), exist in solution as an ensemble of conformations. 17beta-HSD1 catalyzes the last step of the biosynthesis of estradiol and, thus, it is a potentially attractive target for breast cancer treatment. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the conformational transitions of its catalytic cycle, a structural analysis of all available crystal structures was performed and representative conformations were assigned to each step of the putative kinetic mechanism. To cover most of the conformational space, all-atom molecular dynamic simulations were performed using the four crystallographic structures best describing apoform, opened, occluded and closed state of 17beta-HSD1 as starting structures. With three of them, binary and ternary complexes were built with NADPH and NADPH-estrone, respectively, while two were investigated as apoform. Free energy calculations were performed in order to judge more accurately which of the MD complexes describes a specific kinetic step. CONCLUSIONS/SIGNIFICANCE: Remarkably, the analysis of the eight long range trajectories resulting from this multi-trajectory/-complex approach revealed an essential role played by the backbone and side chain motions, especially of the betaF alphaG'-loop, in cofactor and substrate binding. Thus, a selected-fit mechanism is suggested for 17beta-HSD1, where ligand-binding induced concerted motions of the FG-segment and the C-terminal part guide the enzyme along its preferred catalytic pathway. Overall, we could assign different enzyme conformations to the five steps of the random bi-bi kinetic cycle of 17beta-HSD1 and we could postulate a preferred pathway for it. This study lays the basis for more-targeted biochemical studies on 17beta-HSD1, as well as for the design of specific inhibitors of this enzyme. Moreover, it provides a useful guideline for other enzymes, also characterized by a rigid core and a flexible region directing their catalysis.

Dataset Information

Interaction of soy and 17beta-HSD1 gene polymorphisms in the risk of endometrial cancer.

Publications

Interaction of soy and 17beta-HSD1 gene polymorphisms in the risk of endometrial cancer.

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