UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations, and tumor receptor status in breast cancer patients

Sparks, Rachel; Ulrich, Cornelia M.; Bigler, Jeannette; Tworoger, Shelley S.; Yasui, Yutaka; Rajan, Kumar B.; Porter, Peggy L.; Stanczyk, Frank Z.; Ballard‐Barbash, Rachel; Yuan, Xiaopu; Lin, Ming Gang; McVarish, Lynda; Aiello, Erin J.; McTiernan, Anne

doi:10.1186/bcr818

Cited by 79 publications

(65 citation statements)

References 46 publications

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“…First, other genes responsible for estrogen metabolism and environmental factors related to estrogen levels may vary across different racial populations. Although the plasma estradiol level was found to be elevated in carriers of the UGT1A1*28 allele, the elevation was confined to homozygous carriers [22] or postmenopausal women with BMI > 27 kg/m 2 [6]. Second, UGT1A1 may also affect breast cancer development through the bilirubin pathway, as it is the primary isoenzyme responsible for bilirubin glucoronidation [1] and bilirubin is an antioxidant [23].…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and breast cancer risk in Africans

Huo

Kim

Adebamowo

et al. 2007

Breast Cancer Res Treat

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The UDP-glucuronosylatransferase 1A1 (UGT1A1) gene is involved in the metabolism of estrogen and detoxification of potential carcinogens. The number of TA repeats in the promoter region of UGT1A1 has been linked to breast cancer risk, but results varied by race. We performed a comprehensive assessment of genetic polymorphisms in the UGT1A1 gene, and examined these polymorphisms and TA repeats in relation to breast cancer risk in a case-control study in Nigeria. 512 breast cancer cases and 226 community controls were genotyped for UGT1A1. Compared with high-activity TA repeat genotypes, the odds ratios (OR) for low-activity and moderateactivity genotypes were 0.47 (95% confidence interval CI, 0.26-0.83) and 0.64 (95% CI, 0.39-1.06), respectively, in premenopausal women (P = 0.009 for trend), but no association was observed in postmenopausal women (P = 0.24). The effect of TA repeats was also differentiated by age: the OR was 0.39 (95% CI 0.21-0.71) for low-activity genotypes and 0.58 (95% CI 0.33-1.00) for moderate-activity genotypes in women <45 years old (P = 0.002 for trend), but no association was observed in women ≥45 years old (P = 0.15). Haplotype analysis showed that UGT1A1 haplotypes were highly diverse with blocked structures. We found a specific haplotype in block 2 that was significantly associated with a 2.1-fold elevated risk (95% CI 1.05-4.39; P = 0.04). In contrast with previous studies, we found low-activity TA repeat alleles were protective against breast cancer among premenopausal indigenous Africans, suggesting that the role of UGT1A1 in breast cancer development may vary by population, presumably due to different environmental and genetic modifier effects.

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Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and breast cancer risk in Africans

Huo

Kim

Adebamowo

et al. 2007

Breast Cancer Res Treat

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“…Several studies have determined associations between UGT genotypes, steroid hormone glucuronidation, and UGT pharmacogenetics S Nagar and RP Remmel Adapted from Tukey and Strassburg (2000) and Desai et al (2003). risk and incidence of cancer (Lampe et al, 2000;MacLeod et al, 2000;Park et al, 2004;Sparks et al, 2004;Nowell et al, 2005). Another important example is that of all-trans-retinoic acid (ATRA) and its glucuronide (Barua and Sidell, 2004).…”

Section: The Ugt Superfamilymentioning

confidence: 99%

“…However, in a subsequent larger study that analysed 455 Caucasian breast cancer cases and 609 controls, no association between UGT1A1 genotype and breast cancer risk or hormone levels was established . Sparks et al (2004) recently reported a reduced risk for ERÀ breast cancer associated with the UGT1A1*28 genotype. The study enrolled 163 female breast cancer patients, monitored sex hormone levels and genotyped subjects for UGT1A1, 2B4, 2B7, 2B15 and sulfotransferase 1A1.…”

Section: Ugt1a1 Polymorphisms and Cancer: Genotype-phenotype Correlationmentioning

confidence: 99%

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

2006

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The uridine diphosphoglucuronosyltransferases (UGTs) belong to a superfamily of enzymes that catalyse the glucuronidation of numerous endobiotics and xenobiotics. Several human hepatic and extrahepatic UGT isozymes have been characterized with respect to their substrate specificity, tissue expression and gene structure. Genetic polymorphisms have been identified for almost all the UGT family members. A wide variety of anticancer drugs, dietary chemopreventives and carcinogens are known to be conjugated by members of both UGT1A and UGT2B subfamilies. This review examines in detail each UGT isozyme known to be associated with cancer and carcinogenesis. The cancer-related substrates for several UGTs are summarized, and the functionally relevant genetic polymorphisms of UGTs are reviewed. A number of genotype-phenotype association studies have been carried out to characterize the role of UGT pharmacogenetics in several types of cancer, and these examples are discussed here. In summary, this review focuses on the role of the human UGT genetic polymorphisms in carcinogenesis, chemoprevention and cancer risk.

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“…In the study by Guillemette et al [18] which analyzed 200 AA women with invasive breast cancer and 200 matched controls for the UGT1A1 TA repeat promoter polymorphism, they demonstrated that among pre-menopausal AA women, the association was stronger for estrogen receptor (ER)-negative breast cancers (OR 2.1, 95% CI 1.0–4.2; P = 0.04) than for ER-positive breast cancers (OR 1.3, 95% CI 0.6–3.0; P = 0.5) [18]. However, this finding was not observed in a similar finding among a larger study of 455 Caucasian women with breast cancer and 603 women without breast cancer [18,15]. Since UGTs are highly polymorphic, determining whether the UGT1A1 promoter polymorphism may have an impact on clinicopathological factors, is crucial for determining breast cancer risk, treatment response, and clinical outcome of the patient.…”

Section: Discussionmentioning

confidence: 96%

“…Our study demonstrated that UGT1A1 gene expression is decreased in breast cancer cases in comparison to controls in AA and EA female donors who have either the UGT1A1*1/*1 , UGT1A1*1/*28 , UGT1A1*28/*28 , or the UGT1A1*28/*37 genotype. Several populationbased studies have observed differences in the TATA box promoter polymorphisms of UGT1A1 in regards to ethnicity, menopausal, and ER status [15,18,23]. In the study by Guillemette et al [18] which analyzed 200 AA women with invasive breast cancer and 200 matched controls for the UGT1A1 TA repeat promoter polymorphism, they demonstrated that among pre-menopausal AA women, the association was stronger for estrogen receptor (ER)-negative breast cancers (OR 2.1, 95% CI 1.0–4.2; P = 0.04) than for ER-positive breast cancers (OR 1.3, 95% CI 0.6–3.0; P = 0.5) [18].…”

Section: Discussionmentioning

confidence: 99%

Characterization of UDP-glucuronosyltransferase (UGT1A1) Promoter Polymorphisms and Gene Expression on Ethnicity, Stage of Disease, and Menopausal Status in Breast Cancer

Starlard‐Davenport

Word

Lyn‐Cook

2012

J Drug Metab Toxicol

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Estrogen metabolism, catalyzed by UGTs, is a major drug-metabolic pathway that results in inactivation of estrogens and their metabolites. Alterations in UGTs involved in estrogen metabolism, has been suggested to play a role in breast cancer risk. The purpose of this study was to: 1) compare the mRNA expression levels of UGTs involved in estrogen metabolism in human breast tissues from women; 2) compare UGT1A1 mRNA expression to tumor stage, ethnicity, and menopausal status in a group of human breast tumors and normal breast tissues, and 3) investigate the association between variations in the number of TA repeats in the promoter region of UGT1A1 to gene expression. Quantification of UGT mRNA in breast tissues revealed that UGT1A4, UGT1A10, and UGT2B7 mRNA levels were decreased in breast cancers as compared to normal breast tissues. UGT1A1 mRNA levels were also significantly decreased in breast cancers as compared to normal breast tissues (Tumor: 0.5 ± 0.2; Normal: 4.1 ± 1.3, p = 0.0006). UGT1A1 mRNA down-regulation was strongly correlated with postmenopausal status in breast cancer versus controls (p = 0.04). In all the UGT1A1 genotypes observed in our study, the mean mRNA levels was significantly decreased among breast cancer cases as compared to controls for UGT1A1*1/*1 (p = 0.004), UGT1A1*28/*28 (p = 0.03) and UGT1A1*28/*37 (p = 0.06). Our findings demonstrate that further investigations are necessary to determine the role of UGT1A1 in breast carcinogenesis.

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UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations, and tumor receptor status in breast cancer patients

Cited by 79 publications

References 46 publications

Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and breast cancer risk in Africans

Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and breast cancer risk in Africans

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

Characterization of UDP-glucuronosyltransferase (UGT1A1) Promoter Polymorphisms and Gene Expression on Ethnicity, Stage of Disease, and Menopausal Status in Breast Cancer

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