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Association of Genetic Polymorphisms in ESR2, HSD17B1, ABCB1, and SHBG Genes with Colorectal Cancer Risk

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Endocrine-Related Cancer (2011) 18 265–276 Association of genetic polymorphisms in ESR2, HSD17B1, ABCB1, and SHBG genes with colorectal cancer risk J Sainz1*, A Rudolph 2*, R Hein 2, M Hoffmeister 3, S Buch4,5, W von Scho¨nfels6, J Hampe4, C Schafmayer 5,6,HVo¨lzke7, B Frank 3, H Brenner 3,AFo¨rsti1,8, K Hemminki1,8 and J Chang-Claude 2 1Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany 2Division of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany 3Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Bergheimer Straße 20, 69115 Heidelberg, Germany 4Department of General Internal Medicine, University Hospital Schleswig-Holstein, Campus Kiel, House 6, Arnold-Heller-Straße 3, 24105 Kiel, Germany 5POPGEN biobank project, University Hospital Schleswig-Holstein, Campus Kiel, House 3, Arnold-Heller-Straße 3, 24105 Kiel, Germany 6Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, House 18, Arnold-Heller-Straße 3, 24105 Kiel, Germany 7Institute for Community Medicine, University Hospital of the Ernst Moritz Arndt University, Walter Rathenau Strasse 48, 17475 Greifswald, Germany 8Center for Primary Health Care Research, Clinical Research Center, SUS Malmo¨, House 28, 205 02 Malmo¨, Sweden (Correspondence should be addressed to J Chang-Claude; Email: [email protected]) *(J Sainz and A Rudolph contributed equally to this work) Abstract The incidence rates and relative risks for colorectal cancer (CRC) are higher in men than in women. Sex steroids may play a role in this gender-associated difference in CRC risk. This study was conducted to explore the relationship of single nucleotide polymorphisms (SNPs) in steroid hormone signaling (ESR1, ESR2, PGR, NR1I2,andSHBG), phase I- and II-metabolizing enzyme (COMT, HSD17B1, CYP1A1, CYP17A1, CYP1A2, CYP1B1, CYP2C9, CYP3A4, CYP2C19,andGSTP1), and hormone transporter (ABCB1) genes with the risk of CRC in German women and men, separately. From the population-based DACHS study (South Germany), 47 putatively functional SNPs were genotyped in 1798 CRC cases (746 women and 1052 men) and 1810 controls (732 women and 1078 men). Significant allele dose–response associations were observed with ESR2_rs1255998, ESR2_rs928554, HSD17B1_rs605059, and ABCB1_rs2229109 in women (P trendZ0.004, 0.05, 0.03, and 0.05 respectively) and with ABCB1_rs1045642, ABCB1_rs9282564, and SHBG_rs6259 in men (P trendZ0.01, 0.03, and 0.02 respectively). The ESR2_rs1255998_G allele showed the most significant association with risk for CRC in women, with a per-allele odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52–0.88). This finding was replicated in an independent study from North Germany including 1076 female CRC cases and 1151 controls (ORZ0.84, 95% CI 0.71–1.04), yielding a per-allele OR of 0.80 (95% CI 0.69–0.93, P trendZ0.003) in the pooled sample. These findings implicate a role of ESR2 in the risk for developing CRC in women and suggest that HSD17B1, ABCB1,andSHBG genes may contribute to sex steroid-mediated effects on CRC development. Endocrine-Related Cancer (2011) 18 265–276 Introduction of all newly diagnosed carcinomas in the European Colorectal cancer (CRC) is the third most common population in 2008. Men are more likely to develop fatal solid cancer worldwide, and it comprised 13.4% CRC than women with a male–female ratio of w1.4 Endocrine-Related Cancer (2011) 18 265–276 Downloaded from Bioscientifica.comDOI: 10.1530/ERC-10-0264 at 09/23/2021 01:31:09PM 1351–0088/11/018–265 q 2011 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.orgvia free access J Sainz et al.: Estrogen metabolism-related genes and CRC (Ferlay et al.2010). It has also been demonstrated that In an attempt to characterize sex-specific genetic women have a better survival than men (Hendifar et al. factors that may contribute to the known gender 2009). A possible explanation for this sex-associated differences in CRC risk, we conducted a comprehensive difference is that either endogenous or exogenous case–control study (Darmkrebs: Chancen der Verhu¨- estrogen influences normal colonic functionality and tung durch Screening (DACHS) study in Germany) and CRC progression (Koo & Leong 2010). The involve- examined 47 genetic variants within genes that are ment of estrogen in breast, ovarian, and endometrial linked to sex steroid metabolism. Polymorphisms in the cancers is well established (Amant et al. 2005, Reeves ATP-binding cassette, sub-family B (MDR/TAP), et al. 2006, Beral et al. 2007); however, there are many member 1 (ABCB1), COMT, hydroxysteroid 17b controversial hypotheses about how estrogen exerts its dehydrogenase 1 (HSD17B1), CYP1A1, CYP17A1, biological action on colonic epithelial cells. Initially, CYP1A2, CYP1B1, CYP2C9, CYP3A4, GSTP1, cyto- estrogen was suggested to promote proliferation of chrome P450, family 2, subfamily C, polypeptide 19 colon epithelial cells through binding to estrogen (CYP2C19), ESR1, ESR2, PGR, NR1I2,andsex receptor (ER)-1, also called ER-a (Xu & Thomas hormone-binding globulin (SHBG) genes were selected 1994). The identification of ER2 (ER-b)asthe and association with CRC was evaluated separately predominant subtype present in both colon epithelial in women and men. To confirm the main findings, cell lines and human colon epithelium samples (Arai we carried out a replication study in an independent et al.2000, Xie et al. 2004) as well as its down- case–control study from Northern Germany. regulated expression on tumor cells compared with normal have pointed out that ER2 might have a selective and inhibitory effect on the proliferation of Materials and methods colon epithelial cells (Foley et al. 2000). Later on, Study participants and data collection epidemiological and clinical studies have reported that The DACHS study is a population-based case–control postmenopausal women undergoing hormone replace- study conducted in Southwest of Germany, which has ment therapy (HRT) have a decreased risk of previously been described in detail (Brenner et al. developing CRC (La Vecchia et al. 2005, Hoffmeister 2006, Hoffmeister et al. 2009, Frank et al. 2010). et al. 2007). In support of this anti-proliferative action Briefly, CRC cases were recruited from patients who of estrogens in colonic cells, Foley et al. (2000) also received in-patient treatment in a hospital of the reported that ESR2 expression level correlate with Rhein–Neckar–Odenwald region due to a first CRC patient survival. diagnosis of CRC. Controls were frequency-matched Intracellular actions of sex steroids are modulated by according to gender, 5-year age groups, county of receptors and local receptor concentrations at the tissue residence, and were then contacted by mail and and, at a cellular level, strictly controlled by sex steroid follow-up calls. Demographic information as well as transporters as well as phase I- and II-metabolizing information on colonoscopies, diet, anthropometry, enzymes. Increasing evidence suggests that the physical activity, medication (including statins, non- presence of single nucleotide polymorphisms (SNPs) steroidal anti-inflammatory drugs (NSAIDs), meno- within genes coding sex steroid hormone receptors and pausal HRT), reproductive factors, lifestyle factors, transporters and phase I- and II-metabolizing enzymes and family history was collected during a face-to-face might play a relevant role determining CRC risk interview by trained interviewers using a standardized (Bethke et al. 2007), although no genetic variants have questionnaire. To be eligible, participants had to be at clearly been demonstrated to explain the inter- least 30 years old and capable to complete the individual differences in mRNA, protein expression, interview. From January 01, 2003 until December 31, or enzyme activity. So far, epidemiologic studies 2007, 1798 cases and 1810 controls were recruited. investigating polymorphisms in hormone-related genes Written informed consent was obtained from all study and CRC have yielded mostly inconclusive results participants. Approximately, 41% of the participants (Slattery et al. 2005, Bethke et al. 2007, Kiss et al. were women (746 cases and 732 controls). Genomic 2007, Lin et al.2010). A significant gender difference DNA was extracted from peripheral blood mono- was reported in one study where an odds ratio (OR) of nuclear cells (PBMCs) or mouthwash using Flexigene 2.1 (95% confidence interval (CI) 1.2–3.6) for colon Kit 250 (Qiagen) and Qiagen Mini Kit (Qiagen) cancer was found in women carrying two alleles with respectively. For genotyping, CRC cases and controls at least 25 CA repeats in the ESR2 gene, but not in men were randomly distributed on 384-well plates (Slattery et al. 2005). (Applied Biosystems, Foster City, CA, USA). Downloaded from Bioscientifica.com at 09/23/2021 01:31:09PM via free access 266 www.endocrinology-journals.org Endocrine-Related Cancer (2011) 18 265–276 Participants with DNA samples that failed in more done using SNPlex chemistry (Applied Biosystems) than 25% of genotyping assays were excluded (28 on an automated platform in the Institute for cases and 20 controls), assuming poor DNA quality Clinical Molecular Biology at the University Hospital and therefore unreliable measurements. This study Schleswig-Holstein in Kiel. was approved by the Ethics Committees of the University of Heidelberg (Germany) and the State Medical
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  • A Challenge for Medicinal Chemistry by the 17Β-Hydroxysteroid Dehydro

    A Challenge for Medicinal Chemistry by the 17Β-Hydroxysteroid Dehydro

    Send Orders of Reprints at [email protected] 1164 Current Topics in Medicinal Chemistry, 2013, 13, 1164-1171 A Challenge for Medicinal Chemistry by the 17-hydroxysteroid Dehydro- genase Superfamily: An Integrated Biological Function and Inhibition Study S.-X. Lina,b, D. Poiriera and J. Adamskic,d.e aLaboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire (CHU) de Quebec Research Center (CHUL) and Laval University, Québec City, Québec, G1V4G2, Canada; bWHO Collaborating Center for Re- search in Human Reproductive Health, Shanghai, 200031, China; cHelmholtz Zentrum München, Institute of Experi- mental Genetics, Genome Analysis Center, 85764 Neuherberg, Germany; dLehrstuhl für Experimentelle Genetik, Tech- nische Universität München, 85350 Freising-Weihenstephan, Germany; eGerman Center for Diabetes Research (DZD), 85764 Neuherberg, Germany Abstract: Members of the 17-hydroxysteroid dehydrogenase (17-HSD) superfamily perform distinct multiple catalyses by the same enzyme, apparently contradictory to the long-held beliefs regarding the high specificity of enzymes. Surpris- ingly, these multi-catalyses can combine synergistically in vitro and in vivo and their dysfunction may result in the stimu- lation of breast or prostate cancer. 17-HSD1 possesses high estrogen activation activity, while its androgen inactivation is significant for decreasing the week concentration of dihydrotestosterone (DHT) in breast cancer cells, an important fac- tor for cell proliferation. 17-HSD5 can also carry out multiple catalyses in hormone-dependent cancer cells. In addition to 17-HSDs 1 and 5 some other family members possess such dual-activity as well, and their inhibition decreases hor- mone-dependent cancer proliferation. The multi-specificity of 17-HSD1 is structurally based on the pseudo-symmetric androgens that can accommodate the narrow enzyme substrate tunnel by both normal and alternative binding.