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Epidemiology and Prevention |
Departments of Surgery [C-S. H., K-J. C.] and Pathology [S-M. S.], National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan [H-D. C., C-W. C.]; and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [C-W. C., C-Y. S.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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22.5). On the basis of comprehensive profiles of estrogen metabolism, this study supports the possibility that breast cancer can be initiated by estrogen exposure. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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CYP17 encodes the enzyme cytochrome P450c17, which catalyzes steroid 17
-hydroxylase and 17–20 lyase activities at key points in estrogen (estradiol) biosynthesis (10)
. The 5'-untranslated region of CYP17 contains a single-base polymorphism (a T-to-C transition) that creates a SP1-type (CCACC box) promoter (11)
. This change also generates a MspA1 restriction site; therefore, MspA1 digestion identifies two alleles, A1 (wt) and A2 (vt). Because the number of 5' promoter elements correlates with promoter activity, the A2 allele may increase CYP17 expression and thus increase estradiol biosynthesis (12)
. This suggestion is supported by evidence that A2 is associated with elevated levels of circulating estradiol in young women (13)
and is related to a markedly increased risk of advanced breast cancer (12)
.
Hydroxylation of estrogen to hormonally inactive, water-soluble metabolites, HEs, is an important means of eliminating estrogen (6
, 14)
. Oxidation occurs via two major pathways, one of which involves C-2 (and/or C-4) of estradiol, resulting in the formation of the 2-HE and 4-HE, whereas the other involves C-16, resulting in the formation of 16-HE. Whereas 2-HE binds much more weakly to the estrogen receptor, resulting in much weaker hormonal potency, 4-HE and 16-HE retain potent hormonal activity (15, 16, 17)
. Furthermore, 4-HE and 16-HE are able to bind to DNA, creating adducts and subsequently causing gene mutations (5
, 6 , 18
, 19)
. Thus, increased formation of 4-HE and 16-HE has been associated with an elevated risk of breast cancer (6
, 14 , 20
, 21)
. CYP1A1 is among the major enzymes participating in estrogen hydroxylation (6
, 14
, 22)
and thus may play an important role in determining the relative distribution of the metabolites. To date, at least four polymorphisms have been described in the human CYP1A1 gene (23)
. Two of these, m1 (a C substituted for T in the 3'-noncoding region, giving rise to a MspI restriction site) and m2 (a point mutation in codon 462 of exon 7, leading to a substitution of valine for isoleucine), are associated with increased breast cancer risk (22
, 24, 25, 26)
. Because the m2 vt in cancer risk may be unrelated to estrogen metabolism (24
, 25)
, and because our previous study (26)
has shown that m1, but not m2, is related to breast cancer in Taiwan, we focused on the role of the m1 polymorphism in our analysis. CYP1A1 activity is more readily inducible in lymphocytes with the m1 genotype than in wt lymphocytes, resulting in the high inducibility phenotype (27
, 28)
.
O-Methylation mediated by COMT is an important mechanism for inactivating CE, including 2-HE and 4-HE (6 , 14) . Reduced COMT activity might increase the risk of breast cancer, secondary to the accumulation of CE, which causes oxidative DNA damage (6 , 29 , 30) . In addition, 2-HE and 4-HE may be oxidized to CE quinones, which react with DNA to form adduct. These adducts, especially CE-3,4-quinone derived from 4-HE, can cause depurination leaving apurine sites (5) , which is the major type of genetic damage leading to mutation and genomic deletion during tumorigenesis (31) . A G-to-A transition at codon 158 of COMT, which leads to a substitution of methionine for valine (32) , was recently linked to low COMT activity, designated the L (low activity) allele (in contrast to the wt H high activity allele). Three epidemiological studies (9 , 33 , 34) were therefore carried out to examine a possible correlation between low activity genotypes of COMT (L/L or L/H) and breast cancer risk. Two studies (9 , 33) found a positive correlation but gave inconsistent results as to whether it was premenopausal or postmenopausal women who had an elevated risk due to possession of the high-risk genotypes.
The dosage of target agents might affect the associations of cancers with polymorphisms of metabolic genes among different study groups. For example, the greatest incremental lung cancer risk (7-fold) for the high-risk CYP1A1 genotype was seen in light smokers, whereas heavy smokers with this genotype had less than twice the risk of heavy smokers without the genotype (35) . Because Asian women have, on average, 20% lower serum estradiol levels than Western women (36) , elucidating the ethnicity-specific effects of genetic polymorphisms of estrogen-metabolizing genes on cancer risk in Taiwanese women might yield valuable clues on the association of breast tumorigenesis with estrogen. This study reports such an investigation.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Questionnaire.
An experienced research nurse was assigned to administer a structured questionnaire to both case and control subjects. The information collected included age at diagnosis, family history of breast cancer (first-degree relatives), history of breast biopsy, history of breast screening, age at menarche and/or menopause, parity, age at FFTP, number of pregnancies, history of breast feeding, use of oral contraceptives, HRT, history of alcohol consumption and cigarette smoking, ethnic background, residence area, family income, and education level. The BMI and menopausal status were also recorded. Women younger than 55 years who had undergone hysterectomy, but not bilateral oophorectomy, were classified as unknown in terms of menopausal status.
Laboratory Analyses.
A 10-ml sample of peripheral blood collected in acetate-citrate dextrose was obtained from each breast cancer patient before treatment and from each control subject. The buffy coats of these specimens were prepared immediately and stored at -80°C until extraction of the genomic DNA. Genomic DNA was obtained by conventional phenol/chloroform extraction followed by ethanol precipitation and stored at -20°C until genotype analysis.
PCR-based RFLP assays (9
, 12
, 26)
were used to determine the CYP17, CYP1A1, and COMT genotypes (Fig. 1)
of the subjects. To ensure that the observed polymorphisms were specific and were not the results of experimental variation, the results were confirmed by repeating the assay.
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Of particular interest was the relationship between estrogen-metabolizing genes and the risk of breast cancer within categories of risk factors representing different levels of estrogen exposure. We adopted four indices to estimate the estrogen exposure level: (a) total years of estrogen exposure (representing the number of years of exposure to menstrual cycles), which was calculated according to the age at menarche and age at interview for premenopausal women and age at the time of menarche and age at menopause for postmenopausal women; (b) the number of years between menarche and FFTP. A more advanced age at FFTP is generally accepted as a major risk factor for breast cancer. Although the mechanism underlying this association has yet to be defined, experimental studies in rats have shown that full-term pregnancy results in permanent differentiation of the vulnerable breast stem cells, altering subsequent susceptibility to hormones (44) ; this suggests that the period between menarche and the age at FFTP may be also critical; (c) age at menarche. This was used because women whose menarche occurred early have higher levels of estrogen during the menstrual cycle (45) as well as a longer duration of exposure to estrogen; and (d) BMI, because endogenous estrogen is converted and released from adipose tissue. Subsequently, possible modification of risk by estrogen exposure was evaluated by calculating the risk (OR) of breast cancer in relation to the number of high-risk genotypes within different levels (categories) of estrogen exposure indices.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The association between the various polymorphisms and breast cancer varied in women with heterozygous wt genotypes (CYP17 A1/A2, CYP1A1 MspI wt/vt, and COMT H/L). In contrast, the risk of breast cancer was consistently elevated in women harboring homozygous variants of the individual genes (CYP17 A2/A2, CYP1A1 MspI vt/vt, and COMT L/L). Because there is very little conclusive evidence in the literature regarding the phenotypic manifestations of heterozygous wt susceptibility genes, and the absence of a gene-dose effect is common in this type of genotype-based study (33)
, we defined susceptibility genotypes on the basis of the findings observed in the present study. Thus, in the following analyses, homozygous variants of CYP17, CYP1A1, and COMT (CYP17 A2/A2, CYP1A1 MspI vt/vt, and COMT L/L) were considered high-risk genotypes; this basis for definition has been used in previous molecular epidemiological studies. Overall, an increased risk of breast cancer associated with individual high-risk genotypes was found consistently (Table 1)
. Individually, breast cancer risk associated with susceptibility genotypes varied for the three genes and was much higher for COMT (P < 0.05) than for CYP17 (P > 0.05), with an intermediate value for CYP1A1 (P < 0.05). A more obvious increase in risk associated with high-risk genotypes was found in postmenopausal women, and among premenopausal women, all of the high-risk genotypes were positively but insignificantly associated with risk.
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. The high-risk CYP17 and CYP1A1 genotypes played a relatively minor role and were not significantly associated with cancer risk. However, consistent with the findings in Table 1
, the high-risk COMT genotype was strongly associated with breast cancer risk, with an adjusted OR of as high as 4.02. An epidemiological concern of this model is the absence of a significant association between family history and breast cancer. This finding has been confirmed to reflect that a relatively high proportion of control subjects had a family history of breast cancer (26)
, which might be expected because they were selected from a group of women who were probably more concerned about their health (i.e., those attending a self-sponsored health examination clinic). Although this might affect evaluations of genetic factors in breast cancer development, this limitation should apply only to genes with high penetrance, such as BRCA1 and BRCA2. For low penetrance genes, such as CYP17, CYP1A1, and COMT, the effect, if any, might be relatively minor. Furthermore, any such overrepresentation of genetic predisposition in our control subjects might underestimate the ORs, and therefore the ORs contributed by genetic polymorphism determined in our findings would be conservative.
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. The reference group represented women at least risk of exposure to active CE because of lower estrogen synthesis and greater CE inactivation. The presence of at least one putative high-risk genotype was associated with an increased risk of breast cancer. The risk of breast cancer increased significantly as the number of putative high-risk genotypes increased (P = 0.006, based on the Mantel extension test for a linear trend). Notably, none of the controls harbored all three high-risk genotypes. Similarly, none of the controls had the high-risk genotypes of both CYP17 and CYP1A1, although these two genes were considered to predispose to a relatively minor risk compared with that for COMT.
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, which showed that estrogen might modify the association between the number of high-risk genotypes and elevated cancer risk. A consistently significant association of an increased cancer risk predisposed by high-risk genotypes was seen in women with longer years of total estrogen exposure (30 years), greater duration from age at menarche to FFTP (10 years), or younger age at menarche (
13 years; all P < 0.05). In contrast, among women with a shorter duration of estrogen exposure, a shorter duration from menarche to FFTP, or an older age at menarche, there was no significant association (all P > 0.05). Furthermore, the increased cancer risk conferred by high-risk genotypes was significant in women with a higher BMI (22.5), but not in those with a lower BMI (Table 4)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Exposure of the breast epithelium to CE, which is suggested to trigger DNA damage and genetic mutations directly (5, 6, 7) , underlies the tumorigenic mechanism evaluated in the present study. In an attempt to address this issue, we defined the role of susceptibility genotypes as contributing to increased formation of CE via increased biosynthesis of estrogen (CYP17 A2/A2), estrogen hydroxylation (CYP1A1 MspI vt/vt), or decreased inactivation of CE via O-methylation (COMT L/L). Our epidemiological observations fit this model remarkably well. The significant association between the number of high-risk genotypes and breast cancer risk supports the hypothesis that breast cancer can be caused by an initiating effect that is due to CE. The modification of this association by the estrogen exposure profile (i.e., more years of estrogen exposure or early menarche, which implies a higher estrogen level during the menstrual cycle) lends additional support to this hypothesis. These results will shed additional light on our understanding of breast tumorigenesis, because although a link between common carcinogens, including cigarette smoke and environmental polyaromatic hydrocarbons, and breast cancer has been suggested, current views on the DNA-damaging agents responsible for breast cancer initiation have been largely inconclusive. Our findings certainly do not exclude the well-established mechanism by which estrogen triggers cell proliferation and tumor promotion. Rather, because only cells undergoing cell division have the potential to fix genetic damage and to accumulate the genomic instability essential for driving cancer development, the dual role of estrogen as both an initiator (i.e., CE) and a promoter (i.e., estradiol) provides a more direct explanation for breast cancer development.
The most inconsistent findings regarding the association between breast cancer risk and COMT polymorphisms are those on the extent of risk modification by BMI during different menopausal states. Breast cancer risk has been associated with the COMT genotype in three particular subsets of women: (a) postmenopausal women with the highest BMI; (b) postmenopausal women with the lowest BMI; and (c) premenopausal women with the highest BMI (9 , 33) . Various biological effects of CE causing either direct DNA damage, leading to mutation, or, conversely, growth inhibition due to its metabolite, 2-methoxyestradiol (7) , under either high or low estrogen environments have been speculated to partially explain these seemingly opposing findings (33 , 48) . However, these studies considered the effect of COMT in isolation, and the failure to consider the effects of other key factors (e.g., the CYP1A1 and/or CYP17 genotypes) may have resulted in an imprecise estimation of the tumorigenic effect of CE, which may also explain, in part, the inconsistent findings. Our findings, which are based on a more comprehensive picture of the entire estrogen-metabolizing pathway, confirmed only that beast cancer risk is associated with the low activity COMT genotype in women with a high BMI. Aromatase enzyme releases estrogen from adipose tissue into the circulation (48) . Therefore, obese women would have higher levels of circulating estrogen, creating an environment in which the genes participating in the CE production and inactivation pathway are most likely to manifest their tumorigenic effects. Due to the relatively small number of women in this study, further stratification of the study subjects based on their BMI and menopausal status would result in an imprecise estimation of risk. Additional, larger, more powerful studies of women with different menopausal and BMI profiles are needed to address this issue.
If the proposed model of estrogen metabolism correctly describes breast cancer pathogenesis, it would be interesting to examine whether it can explain in part the ethnic variation in breast cancer incidence. The breast cancer incidence in Taiwan (20 of 100,000 women/year) is only about 20–25% that of American whites. However, Taiwanese women have several genetic factors, including higher frequencies of the CYP17 A2 and CYP1A1 MspI vt alleles, that contribute to increased formation of CE, which would seem to increase the risk of tumors and is inconsistent with the low incidence of breast cancer. Our finding that harboring a high-risk COMT genotype is a stronger predictor of breast cancer risk than harboring a high-risk CYP17 or CYP1A1 genotype is therefore particularly intriguing and may indicate that inactivation is more important than formation of CE in breast cancer development in Taiwanese women. It is biologically plausible that the breast cancer predisposition conferred by high-risk genotypes of CYP17 or CYP1A1 in Taiwanese women is minimized because of a relatively low level of estrogen, which could be related to late menarche, early menopause, low fat or cholesterol intake from Eastern diets, or a combination of these factors. On the other hand, the high frequency of high activity alleles/genotypes of COMT in our population [e.g., >95% of controls had H/H or H/L genotypes in this study versus 72–87% in previous reports (9 , 33 , 34) ] should indicate a markedly lower exposure of breast epithelium to CE, which might also explain the reduced risk of breast cancer seen in Taiwanese women.
The present study used a case-control design, which, in theory, might be subject to a variety of biases derived mainly from inappropriate selection of the control group or differential recall bias. However, considerable efforts, including the application of a standardized interview to ensure the validity of information collected by questionnaire, were made to avoid such biases. Our finding that the risk profiles defined in this series of patients (26 , 37 , 41) were similar to those reported in other breast cancer studies and consistent with the current understanding of breast tumorigenesis provides solid justification of the validity of our study results. The major epidemiological consideration, if any, of the present study was the relatively small sample size. However, as compared with other molecular epidemiological studies addressing similar issues, we do not consider our sample size to have been inadequate to assess the associations of interest. In addition, it should be noted that the 150 case subjects included in this study constituted about 8–10% of the total breast cancer patients annually diagnosed in Taiwan. Finally, the proportion of women with the high-risk CYP1A1 or CYP17 alleles was higher in our Taiwanese population than those reported in the Western population. Thus, it should have been easier to obtain adequate statistical power to evaluate the contribution of these two genes. In contrast, only 3–4% of Taiwanese women were found to have the high-risk COMT genotype, which is in sharp contrast to the >10% rate reported in previous studies conducted in white populations. However, in the present study, COMT was found to be the most significant susceptibility gene associated with elevated breast cancer risk in Taiwan. Thus, the problem of sample size should have had only a minor impact on our findings.
In summary, estrogen and other steroid hormones are undoubtedly involved in the pathogenesis and progression of breast cancer. However, the tumorigenic mechanisms underlying their effects are more complex and go beyond the general concept that they stimulate cell proliferation, which in turn leads to neoplasia. In the present study, we demonstrated that breast cancer may be attributable to susceptibility genotypes of estrogen-metabolizing genes, which lead to increased levels of CE. The elevated cancer risk associated with increased exposure to CE mediated by susceptibility genotypes observed in the present study may reflect not only a higher level of potentially carcinogenic CE but also a decrease in anticarcinogenic 2-methoxyestradiol concentration, which is converted from CE by COMT (7)
. Other genes certainly participate in this estrogen-metabolizing pathway. Candidate genes are CYP1B1 (involved in estrogen hydroxylation), 16-hydroxylase (involved in 16-HE formation), or detoxification enzymes in the glutathione S-transferase family (6
, 14)
. A multigenic study on genetic susceptibility with a larger sample size is the best solution to resolve the current inconsistent study results.
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FOOTNOTES |
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1 To whom requests for reprints should be addressed, at Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan. Fax: 886-2-2782-3047; E-mail: bmcys{at}ccvax.sinica.edu.tw 
2 The abbreviations used are: FFTP, first full-term pregnancy; BMI, body mass index; CE, catechol estrogen; CI, confidence interval; HE, hydroxyestrone; HRT, hormone replacement therapy; OR, odds ratio; aOR, adjusted OR; wt, wild-type; vt, variant.
Received 4/ 5/99. Accepted 8/ 6/99.
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A. H. Wu, C.-C. Tseng, D. Van Den Berg, and M. C. Yu Tea Intake, COMT Genotype, and Breast Cancer in Asian-American Women Cancer Res., November 1, 2003; 63(21): 7526 - 7529. [Abstract] [Full Text] [PDF]
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C.-C. Hong, H. J. Thompson, C. Jiang, G. L. Hammond, D. Tritchler, M. Yaffe, and N. F. Boyd Val158Met Polymorphism in Catechol-O-methyltransferase Gene Associated with Risk Factors for Breast Cancer Cancer Epidemiol. Biomarkers Prev., September 1, 2003; 12(9): 838 - 847. [Abstract] [Full Text] [PDF]
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M. Sasaki, M. Kaneuchi, N. Sakuragi, and R. Dahiya Multiple Promoters of Catechol-O-methyltransferase Gene Are Selectively Inactivated by CpG Hypermethylation in Endometrial Cancer Cancer Res., June 15, 2003; 63(12): 3101 - 3106. [Abstract] [Full Text] [PDF]
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Y.-P. Fu, J.-C. Yu, T.-C. Cheng, M. A. Lou, G.-C. Hsu, C.-Y. Wu, S.-T. Chen, H.-S. Wu, P.-E. Wu, and C.-Y. Shen Breast Cancer Risk Associated with Genotypic Polymorphism of the Nonhomologous End-Joining Genes: A Multigenic Study on Cancer Susceptibility Cancer Res., May 15, 2003; 63(10): 2440 - 2446. [Abstract] [Full Text] [PDF]
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S. Wedren, T. R. Rudqvist, F. Granath, E. Weiderpass, M. Ingelman-Sundberg, I. Persson, and C. Magnusson Catechol-O-methyltransferase gene polymorphism and post-menopausal breast cancer risk Carcinogenesis, April 1, 2003; 24(4): 681 - 687. [Abstract] [Full Text] [PDF]
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 I. Gorai, K. Tanaka, M. Inada, H. Morinaga, Y. Uchiyama, R. Kikuchi, O. Chaki, and F. Hirahara Estrogen-Metabolizing Gene Polymorphisms, But Not Estrogen Receptor-{alpha} Gene Polymorphisms, Are Associated with the Onset of Menarche in Healthy Postmenopausal Japanese Women J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 799 - 803. [Abstract] [Full Text] [PDF]
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 S. E. McCann, K. B. Moysich, J. L. Freudenheim, C. B. Ambrosone, and P. G. Shields The Risk of Breast Cancer Associated with Dietary Lignans Differs by CYP17 Genotype in Women J. Nutr., October 1, 2002; 132(10): 3036 - 3041. [Abstract] [Full Text] [PDF]
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 M M de Jong, I M Nolte, G J te Meerman, W T A van der Graaf, J C Oosterwijk, J H Kleibeuker, M Schaapveld, and E G E de Vries Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility J. Med. Genet., April 1, 2002; 39(4): 225 - 242. [Abstract] [Full Text] [PDF]
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 Z. Ye and J. M. Parry The CYP17 MspA1 polymorphism and breast cancer risk: a meta-analysis Mutagenesis, March 1, 2002; 17(2): 119 - 126. [Abstract] [Full Text] [PDF]
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J. A. Lavigne, J. E. Goodman, T. Fonong, S. Odwin, P. He, D. W. Roberts, and J. D. Yager The Effects of Catechol-O-Methyltransferase Inhibition on Estrogen Metabolite and Oxidative DNA Damage Levels in Estradiol-treated MCF-7 Cells Cancer Res., October 1, 2001; 61(20): 7488 - 7494. [Abstract] [Full Text] [PDF]
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J. E. Goodman, J. A. Lavigne, K. Wu, K. J. Helzlsouer, P. T. Strickland, J. Selhub, and J. D. Yager COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk Carcinogenesis, October 1, 2001; 22(10): 1661 - 1665. [Abstract] [Full Text] [PDF]
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R. A. Kittles, R. K. Panguluri, W. Chen, A. Massac, C. Ahaghotu, A. Jackson, F. Ukoli, L. Adams-Campbell, W. Isaacs, and G. M. Dunston CYP17 Promoter Variant Associated with Prostate Cancer Aggressiveness in African Americans Cancer Epidemiol. Biomarkers Prev., September 1, 2001; 10(9): 943 - 947. [Abstract] [Full Text] [PDF]
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 A. Maitra, I. I. Wistuba, C. Washington, A. K. Virmani, R. Ashfaq, S. Milchgrub, A. F. Gazdar, and J. D. Minna High-Resolution Chromosome 3p Allelotyping of Breast Carcinomas and Precursor Lesions Demonstrates Frequent Loss of Heterozygosity and a Discontinuous Pattern of Allele Loss Am. J. Pathol., July 1, 2001; 159(1): 119 - 130. [Abstract] [Full Text] [PDF]
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K. Mitrunen, N. Jourenkova, V. Kataja, M. Eskelinen, V.-M. Kosma, S. Benhamou, D. Kang, H. Vainio, M. Uusitupa, and A. Hirvonen Polymorphic Catechol-O-methyltransferase Gene and Breast Cancer Risk Cancer Epidemiol. Biomarkers Prev., June 1, 2001; 10(6): 635 - 640. [Abstract] [Full Text] [PDF]
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R. Todorovic, P. Devanesan, S. Higginbotham, J. Zhao, M. L. Gross, E. G. Rogan, and E. L. Cavalieri Analysis of potential biomarkers of estrogen-initiated cancer in the urine of Syrian golden hamsters treated with 4-hydroxyestradiol Carcinogenesis, June 1, 2001; 22(6): 905 - 911. [Abstract] [Full Text] [PDF]
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D. Schwarz, P. Kisselev, I. Cascorbi, W.-H. Schunck, and I. Roots Differential metabolism of benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol by human CYP1A1 variants Carcinogenesis, March 1, 2001; 22(3): 453 - 459. [Abstract] [Full Text] [PDF]
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 M. Clemons and P. Goss Estrogen and the Risk of Breast Cancer N. Engl. J. Med., January 25, 2001; 344(4): 276 - 285. [Full Text] [PDF]
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H. S. Feigelson, R. McKean-Cowdin, G. A. Coetzee, D. O. Stram, L. N. Kolonel, and B. E. Henderson Building a Multigenic Model of Breast Cancer Susceptibility: CYP17 and HSD17B1 Are Two Important Candidates Cancer Res., January 1, 2001; 61(2): 785 - 789. [Abstract] [Full Text]
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K. Mitrunen, N. Jourenkova, V. Kataja, M. Eskelinen, V.-M. Kosma, S. Benhamou, H. Vainio, M. Uusitupa, and A. Hirvonen Steroid Metabolism Gene CYP17 Polymorphism and the Development of Breast Cancer Cancer Epidemiol. Biomarkers Prev., December 1, 2000; 9(12): 1343 - 1348. [Abstract] [Full Text]
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J. E. Goodman, J. A. Lavigne, J. G. Hengstler, B. Tanner, K. J. Helzlsouer, and J. D. Yager Catechol-O-Methyltransferase Polymorphism Is Not Associated with Ovarian Cancer Risk Cancer Epidemiol. Biomarkers Prev., December 1, 2000; 9(12): 1373 - 1376. [Abstract] [Full Text]
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 A. B. Spurdle, J. L. Hopper, G. S. Dite, X. Chen, J. Cui, M. R. E. McCredie, G. G. Giles, M. C. Southey, D. J. Venter, D. F. Easton, et al. CYP17 Promoter Polymorphism and Breast Cancer in Australian Women Under Age Forty Years J Natl Cancer Inst, October 18, 2000; 92(20): 1674 - 1681. [Abstract] [Full Text] [PDF]
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T. Habuchi, Z. Liqing, T. Suzuki, R. Sasaki, N. Tsuchiya, H. Tachiki, N. Shimoda, S. Satoh, K. Sato, Y. Kakehi, et al. Increased Risk of Prostate Cancer and Benign Prostatic Hyperplasia Associated with a CYP17 Gene Polymorphism with a Gene Dosage Effect Cancer Res., October 1, 2000; 60(20): 5710 - 5713. [Abstract] [Full Text]
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J. A. Williams and D. H. Phillips Mammary Expression of Xenobiotic Metabolizing Enzymes and Their Potential Role in Breast Cancer Cancer Res., September 1, 2000; 60(17): 4667 - 4677. [Abstract] [Full Text]
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C.-Y. Shen, J.-C. Yu, Y.-L. Lo, C.-H. Kuo, C.-T. Yue, Y.-S. Jou, C.-S. Huang, J.-C. Lung, and C.-W. Wu Genome-wide Search for Loss of Heterozygosity Using Laser Capture Microdissected Tissue of Breast Carcinoma: An Implication for Mutator Phenotype and Breast Cancer Pathogenesis Cancer Res., July 1, 2000; 60(14): 3884 - 3892. [Abstract] [Full Text]
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 J. D. Yager Chapter 3: Endogenous Estrogens as Carcinogens Through Metabolic Activation J Natl Cancer Inst Monographs, July 1, 2000; 2000(27): 67 - 73. [Abstract] [Full Text] [PDF]
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J. Weisz, G. Fritz-Wolz, S. Gestl, G. A. Clawson, C. R. Creveling, J. G. Liehr, and D. Dabbs Nuclear Localization of Catechol-O-Methyltransferase in Neoplastic and Nonneoplastic Mammary Epithelial Cells Am. J. Pathol., June 1, 2000; 156(6): 1841 - 1848. [Abstract] [Full Text] [PDF]
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