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  • 1
    Online Resource
    Online Resource
    The Functional UGT1A1 Promoter Polymorphism Decreases Endometrial Cancer Risk
    American Association for Cancer Research (AACR) ; 2004
    In:  Cancer Research Vol. 64, No. 3 ( 2004-02-01), p. 1202-1207
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 64, No. 3 ( 2004-02-01), p. 1202-1207
    Abstract: UDP-glucuronosyltransferase (UGT) 1A1 is involved in the inactivation of estradiol (E2) and its oxidized metabolites. These metabolites have been shown to contribute to the development of endometrial cancer in animal studies. Thus UGT1A1 represents a candidate gene in endometrial carcinogenesis. In this study, we established the substrate specificity of UGT1A1 for E2 and its 2- and 4-hydroxylated metabolites. Intrinsic clearances indicated that UGT1A1 had a preference for the glucuronidation of 2-hydroxyestradiol, a metabolite associated with antiproliferative activity. Expression analysis demonstrated that UGT1A1 is present in the nonmalignant endometrium. Subsequently, we sought to determine whether the common UGT1A1 promoter allele, UGT1A1*28 [A(TA)7TAA], which decreases gene transcription, was associated with endometrial cancer risk in a case-control study nested within the Nurses’ Health Study (222 cases, 666 matched controls). Conditional logistic regression demonstrated a significant inverse association with the UGT1A1*28 allele and endometrial cancer risk. Compared with women homozygous for the UGT1A1*1 [A(TA)6TAA] allele, the adjusted odds ratio (OR) was 0.81 [95% confidence interval (CI), 0.56–1.16] for the UGT1A1*1/*28 genotype and 0.40 (95% CI, 0.21–0.75) for the homozygous UGT1A1*28 genotype (Ptrend = 0.007). There was a suggestion of an interaction by menopausal status [OR = 0.39 (95% CI, 0.18–0.85) for premenopausal women and OR = 0.79 (95% CI, 0.55–1.13) for postmenopausal women who carry the UGT1A1*28 allele (Pinteraction = 0.05)] . These observations suggest that lower expression of UGT1A1 decreases the risk of endometrial cancer by reducing the excretion of 2-hydroxyestradiol, the antiproliferative metabolite of E2, in the endometrium.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-03-3295
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2004
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Profiling of Endogenous Estrogens, Their Precursors, and Metabolites in Endometrial Cancer Patients: Association with Risk and Relationship to Clinical Characteristics
    The Endocrine Society ; 2011
    In:  Endocrinology Vol. 152, No. 1 ( 2011-01-01), p. 335-335
    Details
    In: Endocrinology, The Endocrine Society, Vol. 152, No. 1 ( 2011-01-01), p. 335-335
    Abstract: Background: Endometrial cancer (EC) predominantly occurs after menopause and is strongly related to steroid hormones, particularly estrogens. However, the relationship between these hormones and clinical characteristics remains unaddressed. Experimental Design: We analyzed the circulating levels of 18 steroids including adrenal precursors, androgens, estrogens, and their glucuronide metabolites, using specific and validated methods based on tandem mass spectrometry. Our goals were to compare circulating levels in postmenopausal women with EC (n = 126) with those of healthy postmenopausal women (n = 110) and to investigate how these hormonal levels relate to clinical characteristics. Results: After adjustment for potential confounders, most hormones were significantly elevated in EC patients compared with healthy controls. In women with type I cancer, estrogen levels were up to 3-fold those of healthy women (P & lt; 0.05). These higher levels were associated with an increased risk of cancer, particularly estrogens and their direct precursors, testosterone and androstenedione (odds ratios ranging from 4.4 to 13.3; P ≤ 0.0003). Elevated circulating levels of estrogens and their metabolites were found in cancer cases with type I endometrioid cancer and low-grade and noninvasive tumor, suggesting an association between these hormones and the tumoral estrogenic activity. In addition, levels of estrone sulfate in EC patients with relapse were 2-fold over levels of EC patients without relapse (P & lt; 0.05), and 4.5-fold over those of healthy women (P & lt; 0.001). Conclusions: Circulating levels of steroids were associated with increased risk of EC. Estrogens may represent novel biomarkers predictive of clinical characteristics, including evidence for an increased risk of relapse.
    Type of Medium: Online Resource
    ISSN: 0013-7227 , 1945-7170
    URL: Article
    DOI: 10.1210/endo.152.1.9998
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2011
    detail.hit.zdb_id: 2011695-0
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  • 3
    Online Resource
    Online Resource
    Specificity and Regioselectivity of the Conjugation of Estradiol, Estrone, and Their Catecholestrogen and Methoxyestrogen Metabolites by Human Uridine Diphospho-glucuronosyltransferases Expressed in Endometrium
    The Endocrine Society ; 2004
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 10 ( 2004-10-01), p. 5222-5232
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 89, No. 10 ( 2004-10-01), p. 5222-5232
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2004-0331
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2004
    detail.hit.zdb_id: 2026217-6
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  • 4
    Online Resource
    Online Resource
    Characterization of Common UGT1A8, UGT1A9, and UGT2B7 Variants with Different Capacities to Inactivate Mutagenic 4-Hydroxylated Metabolites of Estradiol and Estrone
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Research Vol. 66, No. 1 ( 2006-01-01), p. 125-133
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 1 ( 2006-01-01), p. 125-133
    Abstract: The oxidative metabolism of estrone (E1) and estradiol (E2) to form carcinogenic 4-hydroxy-catecholestrogens (4-OHCE) is associated with uterine and breast carcinogenesis. In this study, we conducted functional analyses of genetic variants in the UDP-glucuronosyltransferase UGT1A8, UGT1A9, and UGT2B7 enzymes primarily involved in the inactivation of 4-OHCEs. Compared with UGT2B7*2 (H268Y), UGT2B7*1 exhibited a 2-fold lower efficiency (intrinsic clearance) at conjugating 4-hydroxyestrone and 4-hydroxyestradiol at positions 3 and 4 caused by altered capacities (Vmax) and affinities (Km). The −79 G & gt;A promoter variation, characterizing the UGT2B7*2g haplotype, leads to a 50% reduction of transcription (P & lt; 0.001) in human endometrial carcinoma-1B cells. Furthermore, a & gt;12-fold decreased intrinsic clearance of the *1 proteins was induced by selected amino acid substitutions in UGT1A8 (*3 C277Y) and UGT1A9 (*3 M33T). Frequencies of the low-activity alleles in Caucasians were 45% for UGT2B7*1, 5% for the −79A promoter variant, 1.2% for UGT1A8*3, and 2.2% for UGT1A9*3. Supporting a protective role in two organs sensitive to 4-OHCE–induced damages, the expression of UGT enzymes was shown by immunohistochemistry in normal breast and endometrial tissues and confirmed by Western blotting in a subset of samples. Altogether, findings suggest that specific polymorphisms in UGT genes may modulate the exposure to carcinogenic metabolites of E2 and potentially lead to an altered risk of breast and endometrial cancers in women carrying the variant alleles. (Cancer Res 2006; 66(1): 125-33)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-05-2857
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
    Online Resource
    Profiling of Endogenous Estrogens, Their Precursors, and Metabolites in Endometrial Cancer Patients: Association with Risk and Relationship to Clinical Characteristics
    The Endocrine Society ; 2011
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 96, No. 2 ( 2011-02-01), p. E330-E339
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 96, No. 2 ( 2011-02-01), p. E330-E339
    Abstract: Endometrial cancer (EC) predominantly occurs after menopause and is strongly related to steroid hormones, particularly estrogens. However, the relationship between these hormones and clinical characteristics remains unaddressed. Experimental Design: We analyzed the circulating levels of 18 steroids including adrenal precursors, androgens, estrogens, and their glucuronide metabolites, using specific and validated methods based on tandem mass spectrometry. Our goals were to compare circulating levels in postmenopausal women with EC (n = 126) with those of healthy postmenopausal women (n = 110) and to investigate how these hormonal levels relate to clinical characteristics. Results: After adjustment for potential confounders, most hormones were significantly elevated in EC patients compared with healthy controls. In women with type I cancer, estrogen levels were up to 3-fold those of healthy women (P & lt; 0.05). These higher levels were associated with an increased risk of cancer, particularly estrogens and their direct precursors, testosterone and androstenedione (odds ratios ranging from 4.4 to 13.3; P ≤ 0.0003). Elevated circulating levels of estrogens and their metabolites were found in cancer cases with type I endometrioid cancer and low-grade and noninvasive tumor, suggesting an association between these hormones and the tumoral estrogenic activity. In addition, levels of estrone-sulfate in EC patients with relapse were 2-fold over levels of EC patients without relapse (P & lt; 0.05), and 4.5-fold over those of healthy women (P & lt; 0.001). Conclusions: Circulating levels of steroids were associated with increased risk of EC. Estrogens may represent novel biomarkers predictive of clinical characteristics, including evidence for an increased risk of relapse.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2010-2050
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2011
    detail.hit.zdb_id: 2026217-6
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  • 6
    Online Resource
    Online Resource
    Circulating Estrogens in Endometrial Cancer Cases and Their Relationship with Tissular Expression of Key Estrogen Biosynthesis and Metabolic Pathways
    The Endocrine Society ; 2010
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 95, No. 6 ( 2010-06-01), p. 2689-2698
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 95, No. 6 ( 2010-06-01), p. 2689-2698
    Abstract: Background: Endometrial cancer is the most common gynecological malignancy. Estrogen exposure is strongly associated with endometrial cancer. Whereas this cancer occurs predominantly in postmenopausal women lacking estrogen production by ovaries, the conversion of adrenal androgen-estrogen precursors to estradiol (E2), estrone (E1), and its sulfate (E1-S) has been well documented in peripheral tissues. Experimental Design: We initially explored whether circulating levels of estrogens, measured by validated mass spectrometry assays, differ in women with endometrial cancer (n = 126) compared with healthy women (n = 110). We then evaluated by quantitative real-time PCR from purified RNA whether the expression profile of 19 estrogen-related synthesis and metabolic genes is modified in peritumoral normal endometrium (n = 36) compared with tumoral (n = 49) tissues. Results: In endometrial cancer cases, circulating levels of E1, E2, and E1-S were significantly higher compared with unaffected controls. In agreement with plasma levels, findings support an enhanced biosynthesis of E2 in tumors. The expression of E2 biosynthesis pathways [E1-S (sulfatase) → E1 (17β-hydroxysteroid dehydrogenase) → E2] was shown to predominate in peritumoral normal endometrium and was significantly increased in tumors. In addition, the inactivation pathways mediated by several uridine diphosphate-glucuronosyltransferases were also enhanced in endometrial tumors compared with peritumoral normal endometrium. Conclusion: We concluded that the higher levels of circulating estrogens in women with endometrial cancer are likely associated with an imbalance of multiple biotransformation pathways in endometrial tumor tissues.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jc.2010-2648
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2010
    detail.hit.zdb_id: 2026217-6
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