Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer

Wong, Nan Soon; Seah, Elaine; Wang, Lingzhi; Yeo, Wee Song; Yap, Hui-Kim; Chuah, Benjamin; Lim, Yi-Wan; Ang, Peter; Tai, Bee–Choo; Lim, Robert C.; Goh, Boon-Cher; Lee, Soo‐Chin

doi:10.1097/fpc.0b013e32834a8639

Cited by 35 publications

(36 citation statements)

References 38 publications

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“…Our data indicate that androgenmetabolizing UGTs are also involved, particularly in the context of ERa þ and/or HER2 þ clinical breast cancers, in which relative expression of UGT2B15 and/or UGT2B17 could discern cases with distinct survival outcomes. Although it is tempting to speculate on how relative levels of either enzyme influence steroid intracrinology and hence disease outcome in various breast cancer contexts, it is important to note that UGT2B15 and UGT2B17 have different potencies in the inactivation of androgen hormones and that one or both have been shown to inactivate xenobiotics and drugs relevant to breast cancer, including bisphenol AF (41), exemestane (42), the histone deacetylase inhibitor vorinostat (43), and the major active tamoxifen metabolite, 4-OH-tamoxifen (42,44). , AR þ breast cancer (MCF7, ZR75-1).…”

Section: Discussionmentioning

confidence: 99%

Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17

Selth

Tarulli

et al. 2016

Cancer Research

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Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERa), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDPglucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced diseasespecific survival in distinct molecular subgroups. Expression of these genes was highest in cases positive for ERa. In cell line models, ERa, AR, and the transcription factor FOXA1 cooperated to increase transcription via tandem binding events at their proximal promoters. ERa activity was dependent on FOXA1, facilitated by AR activation, and potently stimulated by estradiol as well as estrogenic metabolites of 5a-dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half-site 3 0 to the FOXA1 and ERa-binding sites. Although AR and FOXA1 bound the UGT promoters in ARpositive/ERa-negative breast cancer cell lines, androgen treatment did not influence basal transcription levels. Ex vivo culture of human breast tissue and ERa þ tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERa binding was evident at the promoters of these genes in a small cohort of primary tumors and distant metastases. Collectively, these data provide insight into sex steroid receptor-mediated regulation of androgen-inactivating enzymes in ERa þ breast cancer, which may have subtypespecific consequences for disease progression and outcomes.

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Section: Discussionmentioning

confidence: 99%

Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17

Selth

Tarulli

et al. 2016

Cancer Research

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“…(Kang et al, 2010;Sadeque et al, 2012). Recently it was discovered that some individuals lack the UGT2B17 gene (Wilson et al, 2004) and that individuals homozygous for the deletion polymorphism excrete androgens and several drugs at a much lower rate compared with those expressing UGT2B17 (Jakobsson et al, 2006;Wong et al, 2011;Wang et al, 2012). The dual role in conjugation of androgens and therapeutic drugs opens the probability of drugendobiotic interaction with the potential risk of endocrine disruption or therapeutic failure.…”

Section: Introductionmentioning

confidence: 99%

Tissue Distribution and Relative Gene Expression of UDP-Glucuronosyltransferases (2B7, 2B15, 2B17) in the Human Fetus

2012

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UDP-glucuronosyltransferases (UGTs) catalyze phase II conjugation reactions and play an important role in the inactivation and elimination of several drugs. It is well known that the UGT activity in fetal livers is low compared with the UGT activity in adult livers. In this study the mRNA expression levels of the three human subfamilies, 2B7, 2B15, and 2B17, were determined in 20 adult and 60 fetal liver tissue specimens. The expression profile in fetal kidneys (N = 43), adrenals (N = 46), and lungs (N = 37) was also determined. All fetal and adult samples were genotyped for the UGT2B17 deletion polymorphism. Adult liver contained 13-36 times higher levels of UGT2B mRNAs as compared with fetal livers. UGT2B7 was most abundant in fetal lungs and kidneys, whereas UGT2B15 and UGT2B17 were predominant in the liver. There was a significant correlation between UGT2B7 expression levels in lungs and kidneys, whereas for the other UGT2Bs no correlation between the different tissues was observed. Fetuses expressing two UGT2B17 alleles (ins/ins) displayed significantly higher levels of UGT2B17 mRNA compared to ins/del fetuses in lungs, whereas in the other tissues no gene dose-effect was observed.

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“…13,14 An influence of UGT2B17 on clinical outcome after vorinostat therapy in Asian women with breast cancer was recently reported. 15 UGT2B17 is affected by a remarkable copy number variation (CNV) spanning a 117-kb region encompassing the entire gene. 16,17 The frequency of copy numbers shows exceptional differences between populations from Africa, Europe, or Asia.…”

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confidence: 99%

Overexpression of uridine diphospho glucuronosyltransferase 2B17 in high-risk chronic lymphocytic leukemia

Gruber

Bellemare

Hoermann

et al. 2013

Blood

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Key Points• Uridine diphospho glucuronosyltransferase 2B17 (UGT2B17) is overexpressed in poor prognostic chronic lymphocytic leukemia.Uridine diphospho glucuronosyltransferase 2B17 (UGT2B17) glucuronidates androgens and xenobiotics including certain drugs. The UGT2B17 gene shows a remarkable copy number variation (CNV), which predisposes for solid tumors and influences drug response. Here, we identify a yet undescribed UGT2B17 mRNA overexpression in poor-risk chronic lymphocytic leukemia (CLL). In total, 320 CLL patients and 449 healthy donors were analyzed. High (above median) UGT2B17 expression was associated with established CLL poor prognostic factors and resulted in shorter treatment-free and overall survival (hazard ratio ([death] 2.18; 95% CI 1.18-4.01; P ‫؍‬ .013). The prognostic impact of mRNA expression was more significant than that of UGT2B17 CNV. UGT2B17 mRNA levels in primary CLL samples directly correlated with functional glucuronidation activity toward androgens and the anticancer drug vorinostat (R > 0.9, P < .001). After treatment with fludarabine containing regimens UGT2B17 was up-regulated particularly in poor responders (P ‫؍‬ .030). We observed an exclusive involvement of the 2B17 isoform within the UGT protein family. Gene expression profiling of a stable UGT2B17 knockdown in the CLL cell line MEC-1 demonstrated a significant involvement in key cellular processes. These findings establish a relevant role of UGT2B17 in CLL with functional consequences and potential therapeutic implications. (Blood. 2013;121(7):1175-1183) IntroductionChronic lymphocytic leukemia (CLL) is characterized by a considerable heterogeneity regarding clinical presentation, need for treatment, and outcome. Many prognostic markers have been identified. 1 Although most of them provide information about risk of progression and survival, the functional role of these markers is often unclear and therapeutic consequences are therefore lacking. Apart from the clinical Rai and Binet staging systems and cytogenetics, 2-4 molecular markers, such as immunoglobulin heavy chain variable (IGHV) gene mutational status 5,6 and lipoprotein lipase (LPL) mRNA expression have strong prognostic value. 7,8 In a pilot gene expression study with 20 CLL patients, we identified a significant association of uridine diphospho (UDP) glucuronosyltransferase 2B17 (UGT2B17) with these prognostic factors. 9 Metabolizing phase 2 enzymes of the UGT2B super-family conjugate various endogenous compounds, in particular steroid hormones as well as several pharmaceutical drugs. 10,11 The UGT2B genes and pseudogenes are clustered on chromosome 4q13 and display up to 95% sequence homology among each other, which is reflected in some overlap in substrate specificity but often distinct expression profile. Isoform UGT2B17 is a major androgen inactivating enzyme playing a role in local tissuespecific regulation of it is substrates. 12 Importantly, antileukemic drugs, such as anthraquinones or the histone deacetylase (HDAC) inhibitor vorinostat, are also subject ...

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Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer

Cited by 35 publications

References 38 publications

Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17

Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17

Tissue Distribution and Relative Gene Expression of UDP-Glucuronosyltransferases (2B7, 2B15, 2B17) in the Human Fetus

Overexpression of uridine diphospho glucuronosyltransferase 2B17 in high-risk chronic lymphocytic leukemia

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