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)

Breast development, one of the first signs of puberty, is closely associated with age at menarche; and early menarche is in turn a well-established risk factor for female breast cancer. We examined the relationships between the onset of puberty and gene variants for certain enzymes that regulate hormone metabolism among 137 healthy nine-year-old girls from two pediatric clinics. High-activity CYP17 alleles, involved in estrogen formation, and high-activity CYP1A2 and CYP1B1 alleles, whose gene products metabolize estradiol, were not associated with pubertal stage. High activity CYP3A4, but not CYP3A5, which primarily metabolizes testosterone, showed a striking association with the onset of puberty (adjusted odds ratio, 3.21; 95% confidence interval, 1.62-6.89 for the genotype 0-1-2 rapid alleles). Of the homozygous CYP3A4*1B/1B girls, 90% had reached puberty; whereas, for the low-activity homozygous CYP3A4*1A/1A individuals, only 40% had done so. In heterozygotes, 56% had reached puberty. CYP1B1, CYP3A4, and CYP3A5 rapid variants were more common in African-American than in Hispanic or Caucasian girls.
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PMID:The CYP3A4*1B variant is related to the onset of puberty, a known risk factor for the development of breast cancer. 1269 7

Variations of estrogen (produced mostly in the ovaries) are under enzymatic influence of aromatases, acting also as oncogenes through the cytochrome CYP17 and CYP19. Their degradation trough methoxylation, resulting in both carcinogenetic and protector compounds, is influenced by 2, 4 and 16 +/- hydrolases. Tissue sensibility to oestrogen depends on the amount of receptors and the plasma level of oestrogen. They are regulating cell's growth and differentiation, depending on subject's age. Paraclinic markers such as the amount of regulating receptors, plasma oestrogen level, breast density and bone density are elements in evaluating breast cancer risk. Among the risk factors of occurrence and development of breast cancer were cited also early menarche, late term pregnancy, late menopause, postmenopausal obesity, smoking and the diet rich in fats and fatty acids, alcohol and antioxidant vitamins.
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PMID:[Breast cancer-estrogens relationship]. 1273 Nov 98

The variant allele(1931C) of CYP17 (1931C/T), which is one of the key enzymes involved in estrogens synthesis, has been shown to be associated with breast cancer risk. Since this variant allele creates an additional putative Sp-1 binding site (CCACC) in the promoter region, it is speculated that it enhances the transcription of CYP17, leading to the enhanced estrogens synthesis in breast tumors. CYP17 messenger RNA (mRNA) expression could be detected in all the normal breast (n=51) and tumor tissues (n=67) by a real-time polymerase chain reaction but CYP17 mRNA expression was not significantly different between the variant allele carriers and non-carriers. In addition, no significant correlation was observed between CYP17 mRNA and E2 levels in tumors, indicating an unimportant role of CYP17 in in situ synthesis of E2. On the other hand, intra-tumoral E2 levels were significantly (P=0.025) higher in the variant allele carriers (127.2+/-11.0 pg/g) than non-carriers (88.2+/-8.5 pg/g). Since it has been previously reported that serum E2 levels are higher in variant allele carriers than non-carriers, it is speculated that the higher intra-tumoral E2 levels in the variant allele carriers might be ascribed to the higher serum E2 levels.
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PMID:Association of CYP17 genetic polymorphism with intra-tumoral estradiol concentrations but not with CYP17 messenger RNA levels in breast cancer tissue. 1276 15

The major known risk factors for female breast cancer are associated with prolonged exposure to increased levels of oestrogen. The predominant theory relates to effects of oestrogen on cell growth. Enhanced cell proliferation, induced either by endogenous or exogenous oestrogens, increases the number of cell divisions and thereby the possibility for mutation. However, current evidence also supports a role for oxidative metabolites, in particular catechol oestrogens, in the initiation of breast cancer. As observed in drug and chemical metabolism, there is considerable interindividual variability (polymorphism) in the conjugation pathways of both oestrogen and catechol oestrogens. These person-to-person differences, which are attributed to polymorphisms in the genes encoding for the respective enzymes, might define subpopulations of women with higher lifetime exposure to hormone-dependent growth promotion, or to cellular damage from particular oestrogens and/or oestrogen metabolites. Such variation could explain a portion of the cancer susceptibility associated with reproductive effects and hormone exposure. In this paper the potential role of polymorphic genes encoding for enzymes involved in oestrogen biosynthesis (CYP17, CYP19, and 17beta-HSD) and conversion of the oestrogen metabolites and their by-products (COMT, CYP1A1, CYP1B1, GSTM1, GSTM3, GSTP1, GSTT1 and MnSOD) in modulating individual susceptibility to breast cancer are reviewed. Although some of these low-penetrance genes appeared as good candidates for risk factors in the etiology of sporadic breast cancer, better designed and considerably larger studies than the majority of the studies conducted so far are evidently needed before any firm conclusions can be drawn.
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PMID:Molecular epidemiology of sporadic breast cancer. The role of polymorphic genes involved in oestrogen biosynthesis and metabolism. 1288 6

The US National Cancer Institute has recently sponsored the formation of a Cohort Consortium (http://2002.cancer.gov/scpgenes.htm) to facilitate the pooling of data on very large numbers of people, concerning the effects of genes and environment on cancer incidence. One likely goal of these efforts will be generate a large population-based case-control series for which a number of candidate genes will be investigated using SNP haplotype as well as genotype analysis. The goal of this paper is to outline the issues involved in choosing a method of estimating haplotype-specific risk estimates for such data that is technically appropriate and yet attractive to epidemiologists who are already comfortable with odds ratios and logistic regression. Our interest is to develop and evaluate extensions of methods, based on haplotype imputation, that have been recently described (Schaid et al., Am J Hum Genet, 2002, and Zaykin et al., Hum Hered, 2002) as providing score tests of the null hypothesis of no effect of SNP haplotypes upon risk, which may be used for more complex tasks, such as providing confidence intervals, and tests of equivalence of haplotype-specific risks in two or more separate populations. In order to do so we (1) develop a cohort approach towards odds ratio analysis by expanding the E-M algorithm to provide maximum likelihood estimates of haplotype-specific odds ratios as well as genotype frequencies; (2) show how to correct the cohort approach, to give essentially unbiased estimates for population-based or nested case-control studies by incorporating the probability of selection as a case or control into the likelihood, based on a simplified model of case and control selection, and (3) finally, in an example data set (CYP17 and breast cancer, from the Multiethnic Cohort Study) we compare likelihood-based confidence interval estimates from the two methods with each other, and with the use of the single-imputation approach of Zaykin et al. applied under both null and alternative hypotheses. We conclude that so long as haplotypes are well predicted by SNP genotypes (we use the Rh2 criteria of Stram et al. [1]) the differences between the three methods are very small and in particular that the single imputation method may be expected to work extremely well.
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PMID:Modeling and E-M estimation of haplotype-specific relative risks from genotype data for a case-control study of unrelated individuals. 1456 96

As a cause of death in women, breast cancer ranks second to stomach cancer in Korea. Age-standardized mortality rates for breast cancer steadily increased during the 1980s and 1990s. There are big differences in the incidence rates for breast cancer compared with Western countries. Epidemiological features, trends in morbidity and mortality, various age-specific incidence curves, migrant study results, and analysis of the risk factors, however, suggest that the incidence of breast cancer might be further increasing in Korea. The key epidemiological hormonal risk factors for breast cancer are all explicable in terms of the estrogen augmented by progesterone hypothesis. These include older age, family history of breast cancer, early menarche, late menopause, late full-term pregnancy, and never a breast feeding. Both the establishment of high-risk groups and the estimation of lifetime risk are essential to develop a control strategy against breast cancer. Invasive ductal carcinoma is the most common histologic type of breast cancer in Korea, and the five-year survival rate has been estimated as 80-83%. Recent studies on the identification of susceptibility factors such as genetic polymorphisms of GSTM1/T1/P1, COMT, CYP2E1, CYP19, CYP17, ER-alpha, XRCC1, XRCC3, RAD52, TGF-alpha, TNF-alpha, IL-1B, IL-1RN, CDK7 etc. that predispose individuals to breast cancer by gene-environment or gene-gene interactions may possibly give further insight into both the etiology and the prevention of this malignancy.
Breast Cancer 2003
PMID:Current researches on breast cancer epidemiology in Korea. 1463 5

Recent success of chemoprevention with tamoxifen has opened a new era wherein prevention of breast cancer is much more emphasized than treatment of established breast cancer. Since tamoxifen has been shown to reduce the risk of estrogen receptor (ER)-positive, but not ER-negative, breast cancer in the chemoprevention trial (P-1), it seems to be important to develop risk factors for ER-positive breast cancer in order to select the candidates for chemoprevention more appropriately. Estrogens, the major risk factors for breast cancer, are speculated to affect breast cancer risk through ER, thus, genetic polymorphisms of the genes involved in the estrogens biosynthesis and metabolism are expected as risk factors for ER-positive breast cancer. Significance of polymorphisms of the genes involved in estrogens biosynthesis (CYP17, CYP19) and metabolism (CYP1A1, CYP1B1, COMT) in modulating the susceptibility to breast cancer is reviewed. The ethnic difference of the variant allele frequencies between Caucasian women and Asian women is also discussed.
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PMID:Polymorphisms of estrogen synthesizing and metabolizing genes and breast cancer risk in Japanese women. 1463 91

Polymorphic alleles of CYP17 and CYP19, which are involved in estrogen biosynthesis, were tested for association with breast cancer (BC). Microsatellite (TTTA)n and 3-bp deletion of CYP19 and single-nucleotide polymorphism T27C of CYP17 were analyzed in 123 BC patients and 119 healthy women. Of the six (TTTA)n alleles observed, allele (TTTA)8 proved to be associated with BC (11.8% vs. 6.3%, P = 0.04). Genotype A2/A2 of CYP17 was also associated with BC (32.5% vs. 20.2%, P = 0.04). Risk of BC was especially high in the presence of both factors (7.3% vs. 0%, P < 0.01). Allele (TTTA)8 and genotype A2/A2 were assumed to be risk factors of BC.
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PMID:[Association of polymorphism of genetic markers of CYP19 and CYP17 with sporadic breast cancer]. 1471 92

Women with high circulating estrogen concentrations have an increased risk of breast cancer; thus, it is important to understand factors, including genetic variability, that influence estrogen concentrations. Several genetic polymorphisms that may influence sex hormone concentrations have been identified, including CYP17 (5'-untranslated region T-->C), CYP19 [intron 4 (TTTA)(n = 7-13) and a 3-bp deletion (-3)], CYP1B1 (Val(432)Leu), and COMT (Val(108/158)Met). We examined associations between these polymorphisms and serum concentrations of estrogens, androgens, and sex hormone-binding globulin and urinary concentrations of 2- and 16alpha-hydroxyestrone in 171 postmenopausal women, using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, not taking hormone therapy, and had a body mass index >24.0. Compared with noncarriers, women carrying two CYP19 7r(-3) alleles had 26% lower estrone (P < 0.001), 19% lower estradiol (P = 0.01), 23% lower free estradiol (P = 0.01), and 22% higher sex hormone-binding globulin concentrations (P = 0.06). Compared with noncarriers, women carrying at least one CYP19 8r allele had 20% higher estrone (P = 0.003), 18% higher estradiol (P = 0.02), and 21% higher free estradiol concentrations (P = 0.01). Women with the COMT Met/Met genotype had 28% higher 2-hydroxyestrone (P = 0.08) and 31% higher 16alpha-hydroxyestrone concentrations (P = 0.02), compared with Val/Val women. Few associations were found for CYP17 and CYP1B1 or with serum androgen concentrations. This study provides further evidence that genetic variation may appreciably alter sex hormone concentrations in postmenopausal women not taking hormone therapy.
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PMID:Association of CYP17, CYP19, CYP1B1, and COMT polymorphisms with serum and urinary sex hormone concentrations in postmenopausal women. 1474 39

This cross-sectional study examined if polymorphisms in genes that code for enzymes involved in the production and metabolism of estrogens are associated with mammographic density, a strong predictor of breast cancer risk. The study included 328 healthy women of different ethnicities who underwent mammographic screening and donated a blood or mouthwash sample for DNA analysis. After digitizing cranio-caudal views of the mammograms, we performed computer-assisted mammographic density assessment. Following DNA extraction, samples were analyzed for polymorphisms in the COMT (Val158Met), CYP1A1 (Ile462Val), CYP1B1 (Val432Leu), CYP1A2 (*1F) and CYP17 (T27C) genes using PCR-RFLP. Breast density was lower in Caucasians than in Asians. Caucasian women were less likely to carry the CYP1A1 variant allele and more likely to carry the variant alleles for CYP1B1 and COMT than women with Asian or Hawaiian ancestry. The low-activity COMT and CYP1A2 variant alleles were weakly related to lower percent mammographic density after adjustment for age, ethnicity, body mass index and reproductive variables (p for gene-dosage =0.08 and 0.05, respectively). These relations were observed in premenopausal women only and were similar in direction and magnitude after stratification by ethnicity. We found no significant associations between breast density and the variant alleles for CYP1A1, CYP1B1 and CYP17. Our data suggest lower mammographic density for women carrying the COMT and CYP1A2 variant alleles than for women carrying the common alleles, though this is the opposite of what is commonly hypothesized from the enzyme function.
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PMID:An investigation of mammographic density and gene variants in healthy women. 1538 51


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