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- Rylander Rudqvist, Tove
(author)
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Extrahepatic cytochrome P450s : relation to cancer susceptibility
- 2003
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Doctoral thesis (other academic/artistic)abstract
- Cytochrome P450 (CYP) enzymes in extrahepatic tissues may play important roles in regulating the capacity of individual cells to metabolize environmental carcinogens and hormones. In this thesis, we characterized the cytochrome P450 profile of the human normal breast and investigated whether polymorphisms in the genes encoding the estrogen metabolizing enzymes CYP1131 and Catechol-O-methyltransferase (COMT) were associated with breast or endometrial cancer risk. We also identified, cloned and characterized the novel extrahepatic cytochrome P450 2S1 (CYP2S1) enzyme with a possible role in metabolism of xenobiotics. Detected levels of CYP enzymes in extrahepatic tissues are generally lower than in the liver and thus difficult to measure. By partial purification of CYPs from breast reduction samples, we spectrally quantified the level in the human normal breast to be approximately 1000-fold lower than in the human liver. We characterized the CYP expression pattern by RTPCR and Western blot in 15 samples and found enzymes involved in the metabolism of environmental carcinogens, steroid hormones and drugs. A large interindividual variation in the expression of CYP1A1, 2A6, 2B6, 2D6 and 3A were shown whereas CYP1B1, 2C, 2E 1, 4A and 19 was present in most samples. Molecular epidemiological studies on the association between polymorphic variants of enzymes involved in estrogen biosynthesis and metabolism and hormonal cancer risk are published with rapidly increasing frequency. However, reported data are generally inconsistent, partly due to small sample sizes. We investigated the association between CYP1B1 and COMT genotypes, respectively, and breast and endometrial cancer (only CYP1B1) in a large population-based case-control study on Swedish postmenopausal women. We genotyped approximately 1 500 breast cancer cases, 690 endometrial cancer cases and 1 500 controls and calculated odds ratios and 95 percent confidence intervals from conditional logistic regression models. We found no overall association between CYP1B1 or COMT genotype and breast cancer risk. Stratified analyses indicated that the CYP1B1*3/*3 genotype may be of importance in conjunction with menopausal hormone use and that the low activity allele of COMT appeared associated with an increased risk for lobular breast cancer. CYP1B1 genotype had no effect on endometrial cancer risk, neither in overall nor in subgroup analyses. The CYP2S1 gene was identified through homology searches with known CYP sequences against the EST database and the high throughput genomic sequences database. The gene was found to be located together with the genes of subfamily CYP2A, CYP2B and CYP2F on chromosome 19. The predicted 504 amino acid sequence displayed 38-49 percent identity with other CYP2 family members and contained the typical structural CYP characteristics; the conserved cystein, the proline rich region and the N-terminal hydrophobic stretch. CYP2S1 mRNA was shown to be highly expressed in lung, trachea, and stomach. The transcript was detected in the liver but at lower levels. A rabbit peptide antiserum against the C-terminus of CYP2S1 recognized a single band in human lung with an apparent molecular weight of 50 kD. Subcellular localization and immunocytochemistry revealed CYP2S1 to be a microsomal protein. High expression in respiratory and gastrointestinal tract indicates a role for this enzyme in extrahepatic: xenobiotic metabolism. Unpublished observations from our lab show that small aromatic hydrocarbons appear to be substrates for CYP2S1. In summary, our work have contributed to the understanding of the presence of CYPs in extrahepatic tissues, particularly breast and lung, and evaluated a possible role for genetic polymorphisms in estrogen metabolism genes in relation to hormonal cancer susceptibility.
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| 2. |
- Rylander-Rudqvist, Tove, et al.
(author)
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Quality and quantity of saliva DNA obtained from the self-administrated oragene method - A pilot study on the cohort of Swedish men
- 2006
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In: Cancer Epidemiology, Biomarkers and Prevention. - Karolinska Inst, Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden. Karolinska Inst, Dept Med Epidemiol & Biostat, KI Biobank, SE-17177 Stockholm, Sweden. : AMER ASSOC CANCER RESEARCH. - 1055-9965 .- 1538-7755. ; 15:9, s. 1742-1745
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Journal article (peer-reviewed)abstract
- Self-collection of saliva has the potential to provide molecular epidemiologic studies with DNA in a user-friendly way. We evaluated the new Oragene saliva collection method and requested saliva samples by mail from 611 men (ages 53-87 years). We obtained a response rate of, on average, 80% [varying from 89% (ages 67-71 years) to 71% (ages 77-87 years)]. DNA was extracted from 90 randomly selected samples, and its usefulness was evaluated with respect to quality, quantity, and whole-genome amplification (WGA). Visual inspection of DNA on agarose gels showed high molecular weight DNA (> 23 kb) and no degradation. Total DNA yield measured with PicoGreen ranged from 1.2 to 169.7 mu g, with a mean of 40.3 mu g (SD, 36.5 mu g) and a median of 29.4 mu g. Human DNA yield was estimated by real-time PCR of the human prothrombin gene to account for 68% (SD, 20%) of total DNA. We did WGA on 81 saliva DNA samples by using the GenomiPhi DNA kit and genotyped both saliva DNA and WGA DNA for 10 single-nucleotide polymorphisms randomly selected from the human genome. Overall genotyping success rate was 96% for saliva DNA and 95% for WGA DNA; 79% of saliva DNA samples and 79% of WGA DNA samples were successfully genotyped for all 10 single-nucleotide polymorphisms. For the 10 specific assays, the success rates ranged between 88% and 100%. Almost complete genotypic concordance (99.7%) was observed between saliva DNA and WGA DNA. In conclusion, Oragene saliva DNA in this study collected from men is of high quality and can be used as an alternative to blood DNA in molecular epidemiologic studies.
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| 3. |
- Suzuki, Reiko, et al.
(author)
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Body weight and postmenopausal breast cancer risk defined by estrogen and progesterone receptor status among Swedish women : A prospective cohort study
- 2006
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In: International Journal of Cancer. - Karolinska Inst, Natl Inst Environm Med, Div Nutrit Epidemiol, S-17177 Stockholm, Sweden. Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. Tokyo Metropolitan Komagome Hosp, Tokyo Metropolitan Canc & Infect Dis Ctr, Div Clin Trials & Res, Tokyo, Japan. : WILEY-LISS. - 0020-7136 .- 1097-0215. ; 119:7, s. 1683-1689
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Journal article (peer-reviewed)abstract
- Although obesity is one of the established risk factors for postmenopausal breast cancer, it is not clear whether this positive association differs across estrogen receptor (ER) and progesterone receptor (PR) status of breast tumors. We evaluated the association between body weight and ER/PR defined breast cancer risk stratified by postmenopausal hormone (PMH) use and a family history of breast cancer in the population-based Swedish Mammography Screening Cohort comprising 51,823 postmenopausal women. Relative body weight was measured by body mass index (kg/m(2)) based on self-reported weight and height collected in 1987 and 1997. Relative risks (RRs) were estimated by hazard ratios derived from Cox proportional hazards regression models. During an average of 8.3-year follow-up, 1,188 invasive breast cancer cases with known ER and PR status were diagnosed. When comparing to normal weight group, we observed a positive association between obesity and risk for the development of ER+ PR+ tumors (RR = 1.67, 95% CI = 1.34-2.07) and an inverse association for the development of all PR- tumors (RR = 0.68, 95 % CI = 0.47-0.98). Statistically significant heterogeneity was observed in the RRs between ER+ PR+ tumors and all PR- tumors (P-heterogeneity < 0.0001). The positive association of obesity with the development of ER+ PR+ tumors was confined to never-users of PMHs (RR = 1.90 (Cl 95%:1.38-2.61)) and to those without a family history of breast cancer (RR = 1.82 (Cl 95%:1.45-2.29)). Our results support the hypothesis that excess endogenous estrogen due to obesity contributes to an increased risk of ER+ PR+ postmenopausal breast cancer. (c) 2006 Wiley-Liss, Inc.
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| 4. |
- Suzuki, Reiko, et al.
(author)
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Dietary fiber intake and risk of postmenopausal breast cancer defined by estrogen and progesterone receptor status - A prospective cohort study among Swedish women
- 2008
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In: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 122:2, s. 403-412
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Journal article (peer-reviewed)abstract
- There is few data on the association between dietary fiber intake and estrogen receptor (ER)/progesterone receptor (PR)-defined breast cancer risk. We evaluated the association between dietary fiber and ER/PR-defined breast cancer risk stratified by postmenopausal hormone use, alcohol intake, and family history of breast cancer in the population-based Swedish Mammography Screening Cohort comprising 51,823 postmenopausal women. Fiber intake was measured by food-frequency questionnaire collected in 1987 and 1997. Relative risks (RRs) were estimated by hazard ratio derived from Cox proportional hazard regression models. During an average of 8.3-year follow-up, 1,188 breast cancer cases with known ER/PR status were diagnosed. When comparing the highest to the lowest quintile, we observed non-significant inverse associations between total fiber intake and the risk of all tumor subtypes; the multivariate-adjusted RRs were 0.85 (95% CI: 0.69-1.05) for overall, 0.85 (0.64-1.13) for ER+PR+, 0.83 (0.52-1.31) for ER+PR- and 0.94 (0.49-1.80) for ER-PR-. For specific fiber, we observed statistically significant risk reductions for overall (34%) and for ER+PR+ (38%) for the highest versus lowest quintile of fruit fiber, and non-significant inverse associations for other subtypes of cancer and types of fiber. Among ever-users of postmenopausal hormone (PMH), total fiber intake and especially cereal fiber were statistically significantly associated with similar to 50% reduced risk for overall and ER+PR+ tumors when comparing the highest to the lowest quartile, but no association was observed among PMH never users. Our results suggest that dietary fiber intake from fruit and cereal may play a role in reducing breast cancer risk. (C) 2007 Wiley-Liss, Inc.
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