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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 ; 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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  • 4
    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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  • 5
    Keywords: RECEPTOR ; CANCER ; tumor ; Germany ; INFORMATION ; POPULATION ; RISK ; TUMORS ; COMPLEX ; COMPLEXES ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; BREAST ; breast cancer ; BREAST-CANCER ; prevention ; PATTERNS ; HEALTH ; AGE ; CIGARETTE-SMOKING ; PROSPECTIVE COHORT ; smoking ; CONSUMPTION ; ESTROGEN-RECEPTOR ; POSTMENOPAUSAL WOMEN ; ONCOLOGY ; case-control study ; PATTERN ; MUTATION CARRIERS ; ALLELES ; HAPLOTYPE ; MOLECULAR-GENETICS ; estrogen receptor ; HAPLOTYPE RECONSTRUCTION ; STEROID-HORMONE RECEPTORS ; HYDROCARBON RECEPTOR ; COFFEE CONSUMPTION ; aromatic and heterocyclic amines ; CAFFEINE CONSUMPTION ; N-acetyltransferase 2 ; N-ACETYLTRANSFERASE-2 GENE
    Abstract: The role of N-acetyltransferase 2 (NAT2) polymorphism in breast cancer is still unclear. We explored the associations between potential sources of exposure to aromatic and heterocyclic amines (AHA), acetylation status and receptor-defined breast cancer in 1020 incident cases and 1047 population controls of the German GENICA study. Acetylation status was assessed as slow or fast. Therefore, NAT2 haplotypes were estimated using genotype information from six NAT2 polymorphisms. Most probable haplotypes served as alleles for the deduction of NAT2 acetylation status. The risks of developing estrogen receptor alpha (ER) and progesterone receptor (PR)-positive or negative tumors were estimated for tobacco smoking, consumption of red meat, grilled food, coffee, and tea, as well as expert-rated occupational exposure to AHA with logistic regression conditional on age and adjusted for potential confounders. Joint effects of these factors and NAT2 acetylation status were investigated. Frequent consumption of grilled food and coffee showed higher risks in slow acetylators for receptor-negative tumors [grilled food: ER-: odds ratio (OR) 2.57, 95% confidence interval (CI) 1.07-6.14 for regular vs. rare; coffee: ER-: OR 2.55, 95% CI 1.22-5.33 for 〉= 4 vs. 0 cups/day]. We observed slightly higher risks for never smokers that are fast acetylators for receptor-positive tumors compared with slow acetylators (ER-: OR 1.32, 95% CI 1.00-1.73). Our results support differing risk patterns for receptor-defined breast cancer. However, the modifying role of NAT2 for receptor-defined breast cancer is difficult to interpret in the light of complex mixtures of exposure to AHA. European Journal of Cancer Prevention 19: 100-109 (C) 2010 Wolters Kluwer Health Lippincott Williams & Wilkins
    Type of Publication: Journal article published
    PubMed ID: 19996973
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  • 6
    Keywords: CANCER ; EXPRESSION ; RISK ; GENE ; SUSCEPTIBILITY ; breast cancer ; PATTERNS ; risk factors ; ESTROGEN-RECEPTOR ; ALLELES ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS ; PROGESTERONE-RECEPTOR ; BRCA2 MUTATION CARRIERS ; Risk prediction
    Abstract: Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 x 10(-18)), rs3803662 (16q12) (P = 3.7 x 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 x 10(-6) and P = 4.1 x 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P 〈= 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P 〈= 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment
    Type of Publication: Journal article published
    PubMed ID: 21596841
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  • 7
    Keywords: case-control studies ; case control study ; case-control study ; population-based case-control study ; OCCUPATIONAL-EXPOSURE ; THERAPIES ; hormone ; breast cancer ; BREAST-CANCER ; HORMONE REPLACEMENT THERAPY ; THERAPY ; EXPOSURE ; NEW-YORK ; RISK
    Type of Publication: Meeting abstract published
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  • 8
    Keywords: RECEPTOR ; CANCER ; carcinoma ; Germany ; PATHWAY ; SYSTEM ; DISEASE ; POPULATION ; RISK ; GENE ; TISSUE ; prognosis ; SEQUENCE ; BREAST ; breast cancer ; BREAST-CANCER ; ASSAY ; NUMBER ; MUTATION ; MUTATIONS ; PREVALENCE ; TRANSFERRIN RECEPTOR ; HEREDITARY HEMOCHROMATOSIS ; ALLELES ; HFE GENE ; IRON
    Abstract: Iron overload has been noticed as a feature of human breast cancer. Cellular iron uptake is regulated by the hemochromatosis and transferrin receptor system, mutations of which cause the iron storage disease hereditary hemochromatosis. To understand the role of hemochromatosis and transferrin receptor system mutations in breast cancer, we analyzed 19 sequence variations at HFE, TFR1, TFR2, and FPN1 and compared genotype frequencies between cases and controls in a German population. There were 688 breast cancer patients and 724 population-based and age-matched controls. For genotyping, we applied the Hemochromatosis Strip Assay and TaqMan allelic discrimination analyses. In addition to genotype frequencies, we established frequencies of compound genotypes. The frequencies of HFE at His63Asp, Ser65Cys, and Cys282Tyr, and of TFR1 at Ser142GIy minor alleles in this German population were 15.9%, 1.8%, 5.6%, and 46.0%, respectively. No rare variants at 15 more loci at HFE, TFR2, and FPN1 were observed in breast cancer patients. There were no significant differences of allele and genotype frequencies between cases and controls. Triple and quadruple compound genotypes at HFE_His63_Cys282-TFR1_Ser142G1y and HFE_His63_-Ser65_Cys282-TFR1_Ser142Gly showed a nonsignificant increase in cases. Although limited by low numbers, an increased prevalence of the HFE Tyr282 minor allele was observed in breast cancer cases with a high number of affected lymph nodes (P = 0.032). Our data suggest that variants of the hemochromatosis-transferrin receptor system have no direct effect on the incidence of breast cancer in Germany. Possible effects on tumor progression and prognosis remain elusive
    Type of Publication: Journal article published
    PubMed ID: 15894659
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  • 9
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; tumor ; BLOOD ; CELL ; Germany ; KINASE ; TYROSINE KINASE ; VITRO ; incidence ; RISK ; GENE ; PROTEIN ; cell line ; DIFFERENTIATION ; TUMORS ; LINES ; PATIENT ; MESSENGER-RNA ; FAMILY ; DONOR ; BINDING ; CELL-LINES ; ASSOCIATION ; FREQUENCY ; polymorphism ; POLYMORPHISMS ; VARIANTS ; FREQUENCIES ; BREAST ; breast cancer ; BREAST-CANCER ; ASSAY ; DESIGN ; MOBILITY ; PROMOTER ; colorectal cancer ; COLORECTAL-CANCER ; mass spectrometry ; CELL-LINE ; LINE ; cancer risk ; REGION ; MASS-SPECTROMETRY ; MIGRATION ; MULTIVARIATE ; LIQUID-CHROMATOGRAPHY ; cell lines ; AFFINITY ; ESTROGEN-RECEPTOR ; MASSES ; ONCOLOGY ; REGRESSION ; RE ; VARIANT ; ALLELE ; regulation ; GENE PROMOTER ; REPORTER GENE ; interaction ; INTERVAL ; ASSAYS ; CELL-DIVISION ; GENOTYPE ; BREAST-TUMORS ; USA ; odds ratio ; cancer research ; RISK-FACTOR ; population-based ; CANCER-RISK ; colorectal ; receptor tyrosine kinase ; RECEPTOR TYROSINE KINASES ; case control ; LOGISTIC-REGRESSION ; DIVISION ; GENETIC-VARIATION ; binding affinity ; COLORECTAL TUMORS
    Abstract: Purpose:The receptor tyrosine kinase ERBB4/HER4 plays a role in cell division, migration, differentiation, as well as apoptosis, and is frequently overexpressed in breast and colorectal tumors. To understand the role of genetic variations in the regulation of ERBB4 expression, we identified new polymorphisms and investigated their functional implication and risk association with breast and colorectal cancer. Experimental Design: We screened colorectal tumors from 92 patients for genetic variants at the ERBB4 ATG -1000 bp 5'-regulatory region by denaturing high-performance liquid chromatography and sequencing. Variants were subjected to DNA-protein interaction analyses (electrophoretic mobility shift assay), reporter gene assays in breast cancer cell lines MDA134 and MDA157, and immunohistochemical analyses of breast tumors. We established genotype frequencies within a breast cancer case-control collection (1,021 cases, 1,015 population-based controls) and a colorectal cancer case-control collection (459 cases, 569 blood donors) using matrix-assisted laser desorption ionization/time of flight mass spectrometry. Adjusted odds ratios (OR) and 95% confidence intervals (Cl) were assessed by multivariate logistic regression. Results: We identified five new germ line variants -815 A 〉 T -782 G 〉 T, -638 insTC, -267 C 〉 G, and -219 del10bp. Two variants showed in vitro functional effects. The -782T allele showed lower protein binding affinity and lower promoter activity compared with the -782G allele, however, the -815T allele showed higher protein binding affinity and higher promoter activity. The -782T variant was identified as a risk allele for breast and colorectal cancer (OR, 1.59; 95% Cl, 1.06-2.34 and OR, 2.21; 95% Cl, 1.22-3.99, respectively). Conclusion: The ERBB4 -782 G 〉 T polymorphism, by virtue of its in vitro functional implication and incidence, is a risk factor for breast and colorectal cancer
    Type of Publication: Journal article published
    PubMed ID: 18094435
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  • 10
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; tumor ; Germany ; THERAPY ; NEW-YORK ; RISK ; GENE ; GENES ; METABOLISM ; TISSUE ; TUMORS ; IMPACT ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; VARIANTS ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; mass spectrometry ; MASS-SPECTROMETRY ; ESTRADIOL ; cytochrome P450 ; ONCOLOGY ; REGRESSION ; RE ; VARIANT ; INCREASE ; MS ; ESTROGEN ; LEVEL ; ENZYME ; GENOTYPE ; MASS ; USA ; population-based ; CYP1B1 ; enzymatic ; E2 ; GENE POLYMORPHISMS ; ESTROGEN-RECEPTOR-ALPHA ; ER alpha status
    Abstract: Cytochrome P450 1B1 (CYP1B1) is a major enzyme in the initial catabolic step of estradiol (E2) metabolism and belongs to the multitude of genes regulated by the estrogen receptor alpha (ER alpha). The common non-synonymous polymorphisms CYP1B1_1358_A 〉 G and CYP1B1_1294_C 〉 G increase CYP1B1 enzymatic activity. Given a relationship between CYP1B1 and breast tumor E2 level as well as E2 level and breast tumor ER alpha expression it is of interest to know whether CYP1B1 polymorphisms have an impact on the ER alpha status of breast cancer. We genotyped the GENICA population-based breast cancer case-control collection (1,021 cases, 1,015 controls) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and investigated in cases the association between genotypes and tumor ER alpha status (739 ER alpha positive cases; 212 ER alpha negative cases) by logistic regression. We observed a significant association between the homozygous variant CYP1B1_1358_GG genotype and negative ER alpha status (P = 0.005; OR 2.82, 95% CI: 1.37-5.82) with a highly significant P (trend) for CYP1B1_1358_A 〉 G and negative ER alpha status (P = 0.003). We also observed an association of CYP1B1_1358_GG and negative PR status (P = 0.015; OR 2.36, 95% CI: 1.18-4.70) and a P-trend of 0.111 for CYP1B1_1358_A 〉 G and negative progesterone receptor (PR) status. We conclude that the CYP1B1_1358_A 〉 G polymorphism has an impact on ER alpha status in breast cancer in that the CYP1B1_1358_GG genotype known to encode higher CYP1B1 activity is associated with ER alpha negativity
    Type of Publication: Journal article published
    PubMed ID: 17922187
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