Identification of UDP-glucuronosyltransferase 1A10 in non-malignant and malignant human breast tissues

Abstract

UGT1A10 was recently identified as the major isoform that conjugates estrogens. In this study, realtime PCR revealed high levels of UGT1A10 and UGT2B7 in human breast tissues. The expression of UGT1A10 in breast was a novel finding. UGT1A10 and UGT2B7 mRNAs were differentially expressed among normal and malignant specimens. Their overall expression was significantly decreased in breast carcinomas as compared to normal breast specimens (UGT1A10: 68 ± 26 vs. 252 ± 86, respectively; p < 0.05) and (UGT2B7: 1.4 ± 0.7 vs. 12 ± 4, respectively; p < 0.05). Interestingly, in African American women, UGT1A10 expression was significantly decreased in breast carcinomas in comparison to normals (57 ± 35 vs. 397 ± 152, respectively; p < 0.05). Among Caucasian women, UGT2B7 was significantly decreased in breast carcinomas in comparison to normals (1.1 ± 0.5 vs. 13.5 ± 6, respectively; p < 0.05). Glucuronidation of 4-OHE 1 was significantly reduced in breast carcinomas compared to normals (30 ± 15 vs. 106 ± 31, respectively; p < 0.05). Differential downregulation of UGT1A10 and UGT2B7 mRNA, protein, and activity in breast carcinomas compared to the adjacent normal breast specimens from the same donor were also found. These data illustrate the novel finding of UGT1A10 in human breast and confirm the expression of UGT2B7. Significant individual variation and down-regulation of expression in breast carcinomas of both isoforms was also demonstrated. These findings provide evidence that decreased UGT expression and activity could result in the promotion of carcinogenesis.

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

“…Our results demonstrate that the mRNA levels of the UGTs analyzed, with the exception of UGT1A8, which was not expressed, are differentially down-regulated in breast cancers as compared to normal breast tissue specimen from AA and EA women in this study. This finding is in agreement with our published study in 2008 [16]. We also showed that UGT1A1 mRNA is significantly decreased in breast tumors compared to normal breast tissues.…”

“…Estrogen metabolism by UGTs is the major drug-metabolic pathway that results in the complete inactivation of estrogens and their hydroxylated metabolites [9–12]. Alterations in UGTs, resulting in decreased UGT expression and glucuronidation activity towards estrogens and their metabolites, has been suggested to play a potential role in breast cancer risk [14–16]. Our previous published study demonstrated that several UGTs, including UGT1A1, are involved in the complete inactivation of both native estrogens and their oxidative metabolites, including the genotoxic 4-OH-E1 [12].…”

“…Our previous published study demonstrated that several UGTs, including UGT1A1, are involved in the complete inactivation of both native estrogens and their oxidative metabolites, including the genotoxic 4-OH-E1 [12]. We also demonstrated for the first time that UGT1A10 was the major UGT involved in estrogen and estrogen metabolite conjugation [16]. Furthermore, we showed that several UGTs, namely UGT1A10 and UGT2B7 were differentially expressed in non-malignant and malignant human breast tissues from AA and EA women [16].…”

“…We also demonstrated for the first time that UGT1A10 was the major UGT involved in estrogen and estrogen metabolite conjugation [16]. Furthermore, we showed that several UGTs, namely UGT1A10 and UGT2B7 were differentially expressed in non-malignant and malignant human breast tissues from AA and EA women [16]. In the present study, we characterized the mRNA expression of UGT1A1, UGT1A4, UGT1A8, UGT1A10, and UGT2B7 in normal and breast tumor tissues from AA and EA women.…”

“…Thus, suggesting that UGTs play a protective role in the breast by terminating or attenuating the biological activities of estrogens and its metabolites. However, modifications in the glucuronidation metabolic pathway, through loss of UGT expression and activity, have been proposed to alter estrogen metabolism, resulting in an increased accumulation of genotoxic estrogen metabolites and risk of breast cancer development [14–16]. For instance, a genetic variant in UGT1A1, which is characterized by the number of TA repeats in the TATA box of the promoter region, has been associated with reduced transcriptional activity towards estrogens in vitro and increased breast cancer risk in several population-based studies [17–20].…”