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  • 1
    Keywords: CANCER ; Germany ; THERAPY ; DENSITY ; COHORT ; HISTORY ; RISK ; FAMILY ; ASSOCIATION ; BREAST ; breast cancer ; BREAST-CANCER ; TRIAL ; family history ; WOMEN ; HORMONE REPLACEMENT THERAPY ; cancer risk ; MAMMOGRAPHY ; case-control studies ; case-control study ; population-based case-control study ; HORMONE-REPLACEMENT THERAPY ; case control studies ; INTERVAL ; SCREEN ; FAMILY-HISTORY ; ESTROGEN PLUS PROGESTIN ; HEALTHY POSTMENOPAUSAL WOMEN ; breast cancer risks ; family history of cancer ; HRT USE ; risk-modifying factors
    Abstract: Objectives: Hormone-replacement therapy (HRT) is an established risk factor for breast cancer. HRT users are different from non-users with respect to socio-economic and other characteristics. There may be women where the HRT-related risk could be modulated by other factors. Methods: We conducted a population-based case-control study with 688 breast cancer cases and 724 controls to characterize HRT users and to estimate odds ratios (OR) and 95% confidence intervals (CI) for HRT use and potentially risk modifying factors. Results: In women aged 50 years and older, 58% of controls and 61% of cases ever used HRT. Among women in natural menopause, HRT use for 10 years and more years was associated with an increased breast cancer risk (OR 1.79, 95% CI, 1.12-2.87), but not among women in surgical menopause (OR 0.61, 95% CI, 0.09-4.17). In the subgroup of women with a positive family history of breast cancer, each year of HRT use increased the risk by 1.22 (95% CI, 1.02-1.47). Another subgroup comprised women with at least 10 diagnostic mammograms (OR 4.04, 95% CI, 1.10-14.81 for using HRT 10 or more years). Conclusions: Long-term HRT use was associated with a breast cancer risk in women with natural menopause. Our findings suggest that this risk may be increased in women with a positive family history of breast cancer and in women who received frequent diagnostic mammographic screens
    Type of Publication: Journal article published
    PubMed ID: 16151884
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  • 2
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; GROWTH ; IN-VITRO ; tumor ; carcinoma ; Germany ; human ; INFORMATION ; ENZYMES ; PROTEIN ; DRUG ; METABOLISM ; DIFFERENTIATION ; TISSUE ; TUMORS ; PATIENT ; prognosis ; ASSOCIATION ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; hormone ; PROGRESSION ; immunohistochemistry ; TUMOR PROGRESSION ; METASTASIS ; cancer risk ; CARCINOMAS ; HUMAN LIVER ; CARCINOGENS ; GST ; ESTROGEN-RECEPTOR ; glutathione-S-transferase ; GLUTATHIONE S-TRANSFERASE ; cytochrome P450 ; FEATURES ; ASSOCIATIONS ; TUMOR-GROWTH ; CARCINOGEN ; ESTROGEN ; ENZYME ; CANCER DEVELOPMENT ; estrogen receptor ; breast carcinoma ; HORMONES ; lymph node ; LYMPH-NODE ; GLUTATHIONE S-TRANSFERASES ; CYP ; CYP1B1 ; CYP3A5 ; CYTOCHROME-P450 ENZYMES ; IMMUNOHISTOCHEMICAL-DEMONSTRATION ; NONTUMOR TISSUES ; progesterone receptor
    Abstract: The potential to metabolize endogenous and exogenous substances may influence breast cancer development and tumor growth. Therefore, the authors investigated the protein expression of Glutathione S-transferase (GST) isoforms and cytochrome P450 (CYP) known to be involved in the metabolism of steroid hormones and endogenous as well as exogenous carcinogens in breast cancer tissue to obtain new information on their possible role in tumor progression. Expression of GST pi, mu, alpha and CYP1A1/2, 1A2, 3A4/5, 1B1, 2E1 was assessed by immunnhistochemistry for primary breast carcinomas of 393 patients from the German GENICA breast cancer collection. The percentages of positive tumors were 50.1 and 44.5% for GST mu and CYP2E1, and ranged from 13 to 24.7% for CYP1A2, GST pi, CYP1A1/2, CYP3A4/5, CYP1B1. GST alpha was expressed in 1.8% of tumors. The authors observed the following associations between strong protein expression and histopathological characteristics: GST expression was associated with a better tumor differentiation (GST mu, p = 0.018) and with reduced lymph node metastasis (GST pi, p = 0.02). In addition, GST mu expression was associated with a positive estrogen receptor and progesterone receptor status (p 〈 0.001). CYP3A4/5 expression was associated with a positive nodal status (p = 0.018). Expression of CYP1B1 was associated with poor tumor differentiation (p = 0.049). Our results demonstrate that the majority of breast carcinomas expressed xenobiotic and drug metabolizing enzymes. They particularly suggest that GST mu and pi expression may indicate a better prognosis and that strong CYP3A4/5 and CYP1B1 expression may be key features of nonfavourable prognosis. (c) 2006 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16721811
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  • 3
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; tumor ; CELL ; Germany ; THERAPY ; DISEASE ; HISTORY ; RISK ; GENE ; GENES ; COMPLEX ; COMPLEXES ; MECHANISM ; FAMILY ; mechanisms ; ASSOCIATION ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; hormone ; NUMBER ; STRESS ; ovarian cancer ; OVARIAN-CANCER ; smoking ; ORAL-CONTRACEPTIVES ; OXIDATIVE STRESS ; body mass index ; glutathione-S-transferase ; PHASE-II ; ONCOLOGY ; ASSOCIATIONS ; LIGHT ; PHASE ; GENOTYPE ; FAMILY-HISTORY ; GLUTATHIONE S-TRANSFERASES ; BODY-MASS ; breast cancer risk ; COLLECTION ; hormone therapy ; Metabolizing enzymes ; METABOLIZING GENES ; GSTs
    Abstract: Breast cancer is a complex disease and in recent years a number of breast cancer susceptibility genes have been identified, but the role of low penetrance susceptibility genes has not been completely resolved. Glutathione S-transferases (GSTs) are phase II xenobiotic metabolizing enzymes involved in the detoxification of chemical carcinogens and environmental pollutants and play an important role in cell defense mechanisms against oxidative stress. They have been in the spot light for the investigation of a potential association with breast cancer risk but so far, sparse or even no data for a potential contribution of GSTA2, GSTM2, GSTO, and GSTZ to breast cancer risk are available. We genotyped GSTA2_448_C 〉 G (rs2180314), GSTA2_742_A 〉 C (rs6577), GSTM2_-832_T 〉 C (rs638820), GSTO1_-1242_G 〉 A (rs2164624), GSTO1_419_A 〉 C (rs4925), GSTO2_-183_A 〉 G (rs2297 235), GSTO2_342_A 〉 G (rs156697), GSTZ1_-4378_A 〉 G (rs1046428), and GSTZ1_94_G 〉 A (rs3177427) by MAL DI-TOF MS in the German GENICA breast cancer case-control collection of 1021 cases and 1015 controls and performed breast cancer risk association in general and with respect to the stratifications: menopausal status, family history of breast or ovarian cancer, use of oral contraceptives, use of hormone therapy, body mass index, and smoking as well as histopathological tumor characteristics including hormone receptor status, grade, histology, and node status. We did not observe any breast cancer risk associations and conclude that it is unlikely that glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 participate in breast cancer susceptibility
    Type of Publication: Journal article published
    PubMed ID: 19859803
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  • 4
    Keywords: APOPTOSIS ; CANCER ; RISK ; METABOLISM ; polymorphism ; breast cancer ; WOMEN ; RANDOMIZED CONTROLLED-TRIAL ; ESTROGEN PLUS PROGESTIN ; CYTOCHROME-P450 ; GENE VARIANT ; 2C19
    Type of Publication: Journal article published
    PubMed ID: 22037784
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  • 5
  • 6
    Keywords: RISK ; ASSOCIATION ; METAANALYSIS ; CHINESE WOMEN ; RECEPTOR STATUS ; MELATONIN ; SHIFT-WORK ; GERMAN GENICA ; CLOCK GENES ; IJAZ S
    Abstract: Objectives: The role of genetic variants and environmental factors in breast cancer etiology has been intensively studied in the last decades. Gene-environment interactions are now increasingly being investigated to gain more insights into the development of breast cancer, specific subtypes, and therapeutics. Recently, night shift work that involves circadian disruption has gained rising interest as a potential non-genetic breast cancer risk factor. Here, we analyzed genetic polymorphisms in genes of cellular clocks, melatonin biosynthesis and signaling and their association with breast cancer as well as gene-gene and gene-night work interactions in a German case-control study on breast cancer. Methods: GENICA is a population-based case-control study on breast cancer conducted in the Greater Region of Bonn. Associations between seven polymorphisms in circadian genes (CLOCK, NPAS2, ARTNL, PER2 and CRY2), genes of melatonin biosynthesis and signaling (AANAT and MTNR1B) and breast cancer were analyzed with conditional logistic regression models, adjusted for potential confounders for 1022 cases and 1014 controls. Detailed shift-work information was documented for 857 breast cancer cases and 892 controls. Gene-gene and gene-shiftwork interactions were analyzed using model-based multifactor dimensionality reduction (mbMDR). Results: For combined heterozygotes and rare homozygotes a slightly elevated breast cancer risk was found for rs8150 in gene AANAT (OR 1.17; 95% CI 1.01-1.36), and a reduced risk for rs3816358 in gene ARNTL (OR 0.82; 95% CI 0.69-0.97) in the complete study population. In the subgroup of shift workers, rare homozygotes for rs10462028 in the CLOCK gene had an elevated risk of breast cancer (OR for AA vs. GG: 3.53; 95% CI 1.09-11.42). Shift work and CLOCK gene interactions were observed in the two-way interaction analysis. In addition, gene-shiftwork interactions were detected for MTNR1B with NPAS2 and ARNTL. Conclusions: In conclusion, the results of our population-based case-control study support a putative role of the CLOCK gene in the development of breast cancer in shift workers. In addition, higher order interaction analyses suggest a potential relevance of MTNR1B with the key transcriptional factor NPAS2 with ARNTL. Hence, in the context of circadian disruption, multivariable models should be preferred that consider a wide range of polymorphisms, e.g. that may influence chronotype or light sensitivity. The investigation of these interactions in larger studies is needed.
    Type of Publication: Journal article published
    PubMed ID: 25229211
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  • 7
    Keywords: APOPTOSIS ; CANCER ; CELL ; Germany ; LUNG-CANCER ; DISEASE ; POPULATION ; RISK ; ENZYMES ; GENE ; transcription ; DNA ; SKIN ; cell cycle ; CELL-CYCLE ; CYCLE ; FREQUENCY ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; IDENTIFICATION ; WOMEN ; DNA-REPAIR ; MUTATION ; REPAIR ; smoking ; SPECTROMETRY ; LINE ; BLADDER-CANCER ; cancer risk ; REGION ; GENOTYPES ; MASS-SPECTROMETRY ; MUTATIONS ; ADDUCTS ; CARRIERS ; case-control studies ; CANCER-RESEARCH ; GERM-LINE ; CYCLE CONTROL ; EXCISION-REPAIR ; DNA-REPAIR GENES ; SKIN-CANCER ; MASSES ; POTENT ; case control study ; case-control study ; VARIANT ; CANCER SUSCEPTIBILITY ; LYS751GLN POLYMORPHISM ; XPD ; XPD POLYMORPHISMS
    Abstract: The polygenic concept of breast cancer susceptibility calls for the identification of genetic variants that contribute to breast cancer risk. Reduced DNA repair proficiencies in women with breast cancer pointed to a possible role of DNA repair enzymes in the risk to develop the disease. The nucleotide excision repair enzyme encoded by the excision repair cross-complementing group 2 gene ERCC2 (formerly XPD) known to cause skin cancer by germ line mutations has multiple regulatory cellular functions, including nucleotide excision repair, basal transcription, cell cycle control, and apoptosis. ERCC2 polymorphisms ERCC2_6540_G〉A (Asp(312)Asn) and ERCC2_18880_A〉C (Lys(751)Gln) within the coding region of this evolutionarily highly conserved gene have been of functional relevance and therefore are potential candidates to confer breast cancer susceptibility. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, we analyzed genotype frequencies in constitutional DNA of study participants of a German case-control study that included 688 cases of incident breast cancer and 724 population-based, age-matched controls. We identified ERCC2_6540_GG (Asp(312)Asp) as an at-risk genotype [odds ratio (OR), 2.06; 95% confidence interval (95% CI), 1.39-3.07]. The ERCC2_6540_GG-associated breast cancer risk was even higher in women who were also carriers of the ERCC2_18880_CC (Gln(751)Gln) genotype (OR, 3.69; 95% CI, 1.76-7.74). We identified ERCC2_6540_G/ERCC2_18880_C (Asp(312)/Gln(751)) as the most potent risk-conferring haplotype (OR, 3.49; 95% CI, 2.30-5.28). To our knowledge, this is the first study assigning breast cancer risk to both the ERCC2 genotype encoding Asp(312)Asp and the haplotype encoding Asp(312)/Gln(751)
    Type of Publication: Journal article published
    PubMed ID: 15598761
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  • 8
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; tumor ; CELL ; FACTOR RECEPTOR ; Germany ; human ; GENE ; GENES ; TUMORS ; MECHANISM ; TRANSCRIPTION FACTOR ; prognosis ; mechanisms ; cell cycle ; CELL-CYCLE ; CYCLE ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; AMPLIFICATION ; mass spectrometry ; cancer risk ; MASS-SPECTROMETRY ; case-control studies ; OVEREXPRESSION ; EPIDERMAL-GROWTH-FACTOR ; CYCLIN D1 ; case-control study ; REGRESSION ; MS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; GENOTYPE ; ADJUVANT CHEMOTHERAPY ; HER2 ; USA ; LOCI ; TRASTUZUMAB ; CCND1 ; breast tumor ; CCND3 ; E2F2 ; HER2 status
    Abstract: Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast tumors is associated with bad prognosis. Therefore, it is highly relevant to further improve understanding of the regulatory mechanisms of HER2 expression. In addition to gene amplification, transcriptional regulation plays a crucial role in HER2 overexpression. In this study, we analyzed 3 polymorphisms E2F2_-5368-A〉G, CCND1-870-A〉G and CCND3_-677_C〉T located in genes involved in cell cycle regulation in the GENICA population-based and age-matched breast cancer case-control study from Germany. We genotyped 1,021 cases and 1,015 controls by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Statistical analyses were performed by conditional logistic regression. We observed no differences in genotype frequencies between breast cancer cases and controls. Subgroup analysis showed associations between carriers of the E2F2_-5368_G allele (OR: 0.60, 95% CI: 0.42-0.85), carriers of the (C) over bar CND (1) over bar _870 G allele (OR: 0.66, 95% CI: 0.45-0.96) and carriers of the -CC (N) over bar D3_-677_T allele (OR: 1.72, 95% CI: 1.20-2.49) and HER2 expression in breast tumors. This finding points to an association of an increased expression of these cell cycle regulators with lower expression of HER2. An explanation for this observation might be that low expression of E2F2, CCND1 and CCND3 decrease levels of factors down-regulating HER2. We conclude that the analyzed polymorphisms located in E2F2, CCND1 and CCAID3 are potential markers for HER2 status of breast tumors. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 19142864
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  • 9
    Keywords: CANCER ; EXPRESSION ; COMBINATION ; Germany ; THERAPY ; LONG-TERM ; RISK ; DRUG ; METABOLISM ; IMPACT ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; SUSCEPTIBILITY ; BREAST ; breast cancer ; BREAST-CANCER ; WOMEN ; mass spectrometry ; cancer risk ; MASS-SPECTROMETRY ; VARIABILITY ; PHENOTYPE ; POSTMENOPAUSAL WOMEN ; MATRIX ; REGRESSION ; THERAPIES ; HORMONE-REPLACEMENT THERAPY ; SUBSTRATE ; ESTROGEN ; TESTS ; USA ; population-based ; CANCER-RISK ; hormone therapy ; ASSISTED-LASER-DESORPTION/IONIZATION ; Genetic ; CURE RATES ; CYP2C19 ; CYTOCHROME-P450 ; DRUG RESPONSE ; GENE VARIANT ; PEPTIC-ULCER ; PROTON PUMP INHIBITORS
    Abstract: Cytochrome P450 2C19 (CYP2C19) plays an important role in the metabolism of xenobiotics and drugs and contributes to the catabolism of endogenous substrates like estradiol. Genetic variability impacts expression and activity of CYP2C19 and therefore can influence catabolism of estrogens. In the present study we analyzed the association of three polymorphisms of CYP2C19 namely CYP2C19*2 (CYP2C19_681_G 〉 A, rs4244285), CYP2C19*3 (CYP2C19_636_G 〉 A, rs57081121) and CYP2C19*17 (CYP2C19_-806_C 〉 T, rs12248560), with breast cancer susceptibility. We genotyped 1,015 breast cancer cases and 1,021 age-matched, population-based controls of the German GENICA study by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. Risk estimates were calculated by logistic regression. All tests were two-sided. We observed a decreased breast cancer risk for carriers of the CYP2C19*17 allele (OR 0.77, 95% CI: 0.65-0.93; P = 0.005). In subgroup analysis we observed a significant decreased breast cancer risk for women using hormone therapy for ten years or longer who were carriers of the CYP2C19*17 allele (OR 0.57, 95% CI: 0.39-0.83; P = 0.003). Since CYP2C19*17 defines an ultra rapid metabolizer phenotype we suggest that an increased catabolism of estrogens by CYP2C19 may lead to decreased estrogen levels and therefore reduces breast cancer risk. This protective effect seems to be stronger in combination with long-term intake of supplemental estrogens during hormone therapy
    Type of Publication: Journal article published
    PubMed ID: 18521743
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  • 10
    Keywords: CANCER ; EXPRESSION ; tumor ; Germany ; MODEL ; MODELS ; SYSTEM ; HISTORY ; RISK ; GENE ; GENES ; PROTEIN ; PROTEINS ; TUMORS ; FAMILY ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; VARIANTS ; BREAST ; breast cancer ; BREAST-CANCER ; TARGET ; TRANSCRIPTIONAL ACTIVITY ; ovarian cancer ; OVARIAN-CANCER ; WOMEN ; p53 ; REGION ; GENOTYPES ; CELL-GROWTH ; ONCOLOGY ; REGRESSION ; ASSOCIATIONS ; VARIANT ; development ; HAPLOTYPE ; FAMILY-HISTORY ; INCREASED RISK ; population-based ; GENETIC-VARIATION ; breast cancer risk ; ESTROGEN-RECEPTOR-ALPHA ; MULTIPLE IMPUTATION ; SUMOYLATION ; Genetic ; tumor grade ; UBC9 and PIAS3 polymorphisms
    Abstract: SUMOylation consists in the covalent conjugation of small ubiquitin-related modifiers to target proteins. SUMOylation participates in processes that are tightly linked to tumorigenesis, and genetic variability in the SUMO-conjugating system may influence the development of breast cancer. We recently reported that variation in the UBC9 gene encoding the SUMO-conjugating enzyme may affect the grade of breast tumors. Following comprehensive in silico analyses for detection of putative functional polymorphisms in 14 genes of the SUMO system, we selected one coding SNP in PIAS3 and seven tag SNPs in UBC9 for association analyses. Results were based on 1,021 cases, and 1,015 matched controls from the population-based GENICA study. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by conditional logistic regression. To explore the association with polymorphisms closely linked to the genotyped variants, multiple imputation based on HapMap data was applied. The study revealed associations of four UBC9 polymorphisms with risk of grade 1 tumors. Comparison of genotype and haplotype models indicated that the best representation of risk solely relied on rs7187167 under dominant penetrance. Women carrying the rare allele showed an increased risk of grade 1 tumors compared with common homozygotes (OR 1.87, 95% CI 1.18-2.95). This effect appeared to be stronger in women with a family history of breast or ovarian cancer. Imputation of polymorphisms in a 300-kb region around the genotyped polymorphisms identified no variants with stronger associations. Our findings suggest that genetic variation in UBC9 may affect the risk of grade 1 breast tumors
    Type of Publication: Journal article published
    PubMed ID: 19760037
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