Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Early age at menarche is a risk factor for breast cancer. A previous study reported a significant positive association between the CYP3A4*1B variant allele and early puberty. We investigated whether polymorphisms of the CYP3A4, CYP17, CYP1B1, and CYP1A2 genes predict the age at onset of menarche. Five hundred eighty-three nulliparous women between ages 17 and 35, of various ethnic backgrounds, completed a questionnaire that included information about menstrual history. Samples of DNA were provided and used to genotype these women for polymorphic variants in the four genes. There was no significant difference in mean age at menarche between women who carried two variant CYP17 A2 alleles (12.5 years) and women who carried one or no variant allele (12.5 years) (P = 0.8, adjusted for ethnic group and year of birth). Similar results were found for the CYP1B1*3 variant allele and for the CYP1A2*1F variant allele. Women who carried two variant CYP3A4*1B alleles had an earlier mean age at menarche (12.0 years) than women who carried one or no variant allele (12.6 years) (P = 0.02). However, after adjusting for ethnic group and year of birth, no significant differences in mean age at menarche were found. The polymorphic variants of the CYP3A4, CYP17, CYP1B1, and CYP1A2 genes are unlikely to influence age of menarche.
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PMID:CYP gene polymorphisms and early menarche. 1174 50

New methods in treatment of hormone-dependent diseases like prostate or breast cancer have become a major subject in medical and pharmaceutical research. Because of the direct correlation of cancer growth and hormone concentration, inhibition of hormone biosynthesis presents a promising strategy in cancer therapy. The key enzyme in androgen biosynthesis is the 17 alpha-hydroxylase-17,20-lyase a cytochrome P450 system, which specifically converts gestagens to androgens. Because the 3D-structure of the enzyme is still unknown most recently a ligand-based design was used to gain deeper insights into protein structure and function. In this paper we present molecular modelling studies on compounds acting as competitive inhibitors of the human 17 alpha-hydroxylase-17,20-lyase. The compounds developed by Hartmann et al. belong to two different structural classes and show a wide range of inhibitory potency. The physico-chemical properties of the molecules were investigated and compared by studying structural flexibility and by calculating molecular interactions fields. The superimposition of all inhibitors in a low energy conformation yielded in the common pharmacophore. In the second part of the paper individual inhibitors were docked into the active site of the enzyme model of CYP17 developed in our group. The dynamic behaviour and stability of the protein-inhibitor-complexes was studied. The protein ligand interactions observed in course of the molecular dynamics simulations correspond well with the experimental data.
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PMID:Investigations on inhibitors of human 17 alpha-hydroxylase-17,20-lyase and their interactions with the enzyme. Molecular modelling of 17 alpha-hydroxylase-17,20-lyase, Part II. 1181 65

Inter-individual differences in susceptibility to breast cancer are partially mediated through the levels of endogenous and exogenous steroid hormones. The CYP17 gene encodes P450c17alpha, an enzyme that is involved in the metabolism of steroid hormones. Increased endogenous steroid hormone levels have been associated with a MspA1 polymorphism in the 5'-promoter region of the CYP17 gene. The CYP17 MspA1 polymorphism has been postulated as being associated with the risk of developing breast cancer. However, the association between the CYP17 MspA1 polymorphism and breast cancer risk has been controversial in the literature. To re-examine this controversy, we have undertaken a meta-analysis of 15 case-control studies, which included a total of 4227 breast cancer cases and 4730 individual controls. The odds ratio (OR) was used to evaluate the risk of breast cancer for each study, using homozygosity of the wild-type allele as the control group. Statistical analysis showed no evidence of heterogeneity within the studies. The pooled ORs of breast cancer associated with the combined variant (A1/A2 + A2/A2) and the homozygous genotype (A2/A2) were 0.98 (95% CI 0.89-1.07) and 1.05 (95% CI 0.87-1.21), respectively. Similarly, the pooled ORs of advanced breast cancer associated with the combined variant and the homozygous genotype were 0.96 (95% CI 0.77-1.20) and 0.88 (95% CI 0.55-1.41), respectively. A pooling of the studies was also conducted for the various ethnic groups, but failed to show an association of CYP17 MspA1 polymorphism with breast cancer risk in the different ethnic groups. In addition, our results show that a possible protective effect for breast cancer risk of a later age at menarche was mainly limited to women with the A1 homozygous genotype. The OR for age at menarche (> or = 13) was 0.87 (95% CI 0.62-1.17). Our results suggest that CYP17 MspA1 polymorphism may be at best a weak modifier of breast cancer risk but is not a significant independent risk factor.
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PMID:The CYP17 MspA1 polymorphism and breast cancer risk: a meta-analysis. 1220 34

Initiation and/or promotion of endometrial cancer is known to be associated with estrogen and androgen (androstenedione) excess as well as with hyperinsulinemia/insulin resistance. It is possible that some allelic polymorphisms of the genes involved in steroidogenesis or steroid metabolism contribute to endometrial cancer susceptibility. We evaluated here the role of CYP17 biallelic (MspAI) polymorphism in 114 endometrial cancer patients compared with 182 healthy women. Our data demonstrated that A2/A2 CYP17 genotype, considered on the basis of initial breast cancer studies as 'unfavorable', was under-represented in endometrial cancer group (odds ratio 0.48, 95% confidence interval 0.25-0.89) that confirmed results of two other recent investigations. Carriers of this genotype were characterized by having lower blood insulin (by 120 min of oral glucose tolerance test 36.7+/-3.9 microU/ml vs. 90.4+/-16.7 microU/ml in postmenopausal women with A1/A1 genotype, P=0.04) and C-peptide levels (after night fasting 575.2+/-78.3 pg/ml vs. 978.9+/-115.7 pg/ml, respectively, P=0.04). No significant difference was found between the mean concentrations of testosterone, dehydroepiandrosterone sulfate and estradiol concentrations in patients-carriers of separate CYP17 genotypes. Thus, CYP17 polymorphism (namely, carrying the 'normal' A1/A1 genotype) might be one of the risk factors for endometrial cancer development. A1/A1 CYP17 variant may be associated with untraditional (non-steroidal) pathways that calls for corresponding preventive measures in high-risk groups.
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PMID:CYP17 genetic polymorphism in endometrial cancer: are only steroids involved? 1191 69

Somatic genetic alterations in tumors are known to correlate with survival, but little is known about the prognostic significance of germ-line variation. We assessed the effect of germ-line variation on survival among women with breast cancer participating in a British population-based study. Up to 2430 cases for whom current vital status data were available were screened for BRCA1/2 mutations and genotyped for polymorphisms in 22 DNA repair, hormone metabolism, carcinogen metabolism, and other genes. The effect of genotype on outcome was assessed by Cox regression analysis. The largest effect was observed for the silent polymorphism D501D (t>c) in LIG4, a gene involved in DNA double-strand break repair. The estimated hazard ratio (HR) in cc homozygotes relative to tt homozygotes was 4.0 (95% confidence interval, 2.1-7.7; P = 0.002), and this effect remained after stratification by stage, grade, and tumor type [HR, 4.2 (1.8-9.4); P = 0.01]. Total length of a CYP19 IVS4 (ttta)(n) repeat was also associated with survival [HR, 0.9 (0.8-1.0); P = 0.01], but this became nonsignificant after stratification by stage, grade, and tumor type. Poorer survival was observed for 10 BRCA1 mutation carriers [HR, 4.1 (1.3-13); P = 0.047]; however, after adjustment for known prognostic factors, the HR estimate decreased to 2.0 and became nonsignificant (P = 0.4). CYP17 (P = 0.05) and TP53 (P = 0.06) polymorphisms showed marginally significant associations in unstratified analyses. No effect on survival was seen for polymorphisms in ATM, BRCA1/2, CHK2, KU70, NBS1, RAD51, RAD52, XRCC3, AR, COMT, NQO1, VDR, ADH3, CYP1A1, GSTP1, TGF-beta, or CDH1. Even if confirmed, the prognostic markers identified in this study are unlikely to replace current markers of prognosis such as estrogen receptor status. However, our results demonstrate the potential of the analysis of germ-line variation to provide insight into the biological determinants of response to treatment and prognosis in breast cancer.
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PMID:Effect of germ-line genetic variation on breast cancer survival in a population-based study. 1203 13

Breast cancer is the most prevalent cancer among women in Western countries, and its prevalence is also increasing in Asia. The major risk factor for breast cancer can be traced to reproductive events that influence the lifetime levels of hormones. However, a large percentage of breast cancer cases cannot, be explained by these risk factors. The identification of susceptibility factors that predispose individuals to breast cancer (for instance, if they are exposed to particular environmental agents) could possibly give further insight into the etiology of this malignancy and provide targets for the future development of therapeutics. The most interesting candidate genes include those that mediate a range of functions. These include carcinogen metabolism, DNA repair, steroid hormone metabolism, signal transduction, and cell cycle control. we conducted a hospital-based case-control study on South Korea to evaluate the potential modifying role of the genetic pollymprphisms of selected low penetrance gens that are involved carcinogen metabolisms (i.e., CYP1A1, CYP2E1, GSTM1/T1/P1, NAT1/2, etc.), estrogen synthesis and metabolism (i.e., CYP19, CYP17, CYP1B1, COMT, ER-alpha, etc.), DNA repair (i.e., XRCC1/3, ERCC2/4, ATM, AGT, etc.), and signal transduction as well as others (i.e., TGF- beta, IGF-1, TNF- beta, IL-1B, IL-1RN, etc.). We also took into account the potential interaction between these and the known risk factors of breast cancer. The results of selected genes will be presented in this mini-review.
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PMID:Genetic polymorphisms and cancer susceptibility of breast cancer in Korean women. 1254 72

Reasons for the recent trend of increasing breast cancer incidence among Chinese and other Asian women are not well understood. Endogenous estrogen levels are strongly associated with breast cancer risk and its determinants include both genetic and lifestyle factors. We conducted a nested case-control study to investigate, within the Singapore Chinese Health Study Cohort, the relationships between polymorphisms in 2 genes involved in estrogen metabolism, CYP17 and HSD17B1, and the risk of breast cancer. For this analysis, 188 incident breast cancer cases and 671 female cohort control subjects were compared. When the HSD17B1 A allele was considered as the "putative high-risk" allele, there was a modest increased risk (adjusted relative risk, RR=1.37, 95% CI=0.90-2.07 for HSD17B1 AA vs. other); this association was statistically significant in analysis restricted to postmenopausal women (RR=1.86, 95% CI=1.14-3.03). There was no significant association between the CYP17 MspAI polymorphism and risk in all subjects (RR=1.06, 95% CI=0.65-1.74 for CYP17 A2A2 vs. CYP17 A1A1) or in postmenopausal women only. When we evaluated breast cancer risk in relation to the joint stratification of CYP17 and HSD17B1 genotypes and according to the combined number of putative high-risk alleles (range, 0-4), we observed an elevated joint effect of the CYP17 and HSD17B1 genes on risk. Women who possessed all 4 putative high-risk alleles of both genes (CYP17 A2A2 and HSD17B1 AA) vs. less displayed a nearly 2-fold increased risk (RR=1.83, 95% CI=0.97-3.44); this finding was statistically significant in postmenopausal women (RR=2.31, 95% CI=1.07-4.98). Risk of breast cancer was similar among women possessing the other genotypes (i.e., less than 4 putative high-risk alleles in the joint CYP17/HSD17B1 genotypes). In addition, the significant increased risk of breast cancer associated with nulliparity or late age at first live birth (age 31 years or older) was largely limited to women with the high-risk CYP17 A1A2/A2A2 or HSD17B1 AA genotypes (RR=2.41, 95% CI=1.56-3.72; RR=4.39, 95% CI=1.71-11.30, respectively). The latter gene-parity effects were especially pronounced in postmenopausal women.
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PMID:HSD17B1 and CYP17 polymorphisms and breast cancer risk among Chinese women in Singapore. 1258 42

Mammographic density has been linked with exposure to endogenous and exogenous steroid hormones, and increased breast cancer risk. Variation in breast density may be due, in part, to polymorphisms in steroid hormone biosynthesis, metabolism and signaling genes. We conducted cross-sectional analyses within the Nurses' Health Study (n = 538), to investigate variation in mammographic breast density, by 10 polymorphisms in eight candidate genes (CYP17, CYP19, CYP1A1, CYP1B1, COMT, UGT1A1, AR, and AIB1). Breast density was assessed using a computer-assisted technique. We evaluated whether associations between variant alleles of these genes and breast density differed by menopause and postmenopausal hormone (PMH) use. Polymorphisms in CYP17, CYP19, CYP1B1, COMT CYP1A1, or AR were not associated consistently with breast density among premenopausal or postmenopausal women. Premenopausal women with the 7/7 UGT1A1 genotype had lower breast density (difference compared to the 6/6 genotype of: -16.5% density; p = 0.04). In contrast, postmenopausal women with the 7/7 UGT1A1 genotype had greater breast density compared to those with the 6/6 genotype (+6.2% density; p = 0.05); this association was strongest among current PMH users (+13.0% density; p = 0.03). In analyses limited to postmenopausal women, breast density was also greater among women carrying short AIB1 alleles (< or = 26 glutamine repeats; +4.1% density; p = 0.04). Most of the variants in the candidate breast cancer genes evaluated in this study are not strong predictors of breast density. However, our findings of differences in associations for UGT1A1 and AIB1 genotypes with breast density by menopausal status needs additional corroboration.
Breast Cancer Res Treat 2003 Jan
PMID:Polymorphisms in steroid hormone pathway genes and mammographic density. 1260 2

A T-C polymorphism in the promoter region of the CYP17 gene has been associated with male and female breast cancer risk as well as early-onset familial breast cancer. The potential role of this polymorphism was investigated in relation to breast cancer risk in Icelandic male and female carriers and noncarriers of a BRCA2 mutation. The study population consisted of 39 male and 523 female breast cancer cases and 309 male and 395 female controls. Of the cases, 15 males and 55 females carried a BRCA2 mutation. We did not find a significant association between male breast cancer risk and CYP17 genotypes. Among male breast cancer cases, the frequency of the CC genotype was higher among carriers of the 999del5 mutation (33.3%) than noncarriers (16.7%), although this difference also did not reach a statistical significance. No association was observed with breast cancer risk among females irrespective of menopausal status, stage of the disease or BRCA2 status. Our findings do not indicate a role for the CYP17 T-C polymorphism in female breast cancer, but a role in male carriers of a BRCA2 mutation could not be excluded because of the small sample size.
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PMID:CYP17 promoter polymorphism and breast cancer risk in males and females in relation to BRCA2 status. 1264 32

Various statistical methods have been proposed to evaluate associations between measured genetic variants and disease, including some using family designs. For breast cancer and rare variants, we applied a modified segregation analysis method that uses the population cancer incidence and population-based case families in which a mutation is known to be segregating. Here we extend the method to a common polymorphism, and use a regressive logistic approach to model familial aggregation by conditioning each individual on their mother's breast cancer history. We considered three models: 1) class A regressive logistic model; 2) age-of-onset regressive logistic model; and 3) proportional hazards familial model. Maximum likelihood estimates were calculated using the software MENDEL. We applied these methods to data from the Australian Breast Cancer Family Study on the CYP17 5'UTR T-->C MspA1 polymorphism measured for 1,447 case probands, 787 controls, and 213 relatives of case probands found to have the CC genotype. Breast cancer data for first- and second-degree relatives of case probands were used. The three methods gave consistent estimates. The best-fitting model involved a recessive inheritance, with homozygotes being at an increased risk of 47% (95% CI, 28-68%). The cumulative risk of the disease up to age 70 years was estimated to be 10% or 22% for a CYP17 homozygote whose mother was unaffected or affected, respectively. This analytical approach is well-suited to the data that arise from population-based case-control-family studies, in which cases, controls and relatives are studied, and genotype is measured for some but not all subjects.
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PMID:Regressive logistic and proportional hazards disease models for within-family analyses of measured genotypes, with application to a CYP17 polymorphism and breast cancer. 1265 20


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