Abstract 4120: UDP-Glucuronosyltransferase 1 (UGT1A1) down-regulation correlates to menopausal status and stage of disease in human breast cancer tissues

Abstract

Abstract Estrogen metabolism, catalyzed by UGTs, is a major drug-metabolic pathway that results in the complete inactivation of estrogens and their hydroxylated metabolites. 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. The purpose of this study was to: 1) compare the mRNA expression levels of UGTs responsible for conjugating estrogens in human breast cancers and normal breast tissues from women; 2) compare UGT1A1 mRNA expression to tumor stage, ER status, 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, UGT1A9, 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 (N = 17) as compared to normal breast tissues (N = 30) (p = 0.02). UGT1A1 down-regulation strongly correlated with menopausal status (premenopausal vs. postmenopausal; p = 0.04) and stage of breast disease (p = 0.01). This may account for variations in response to chemotherapy used for the treatment of more aggressive breast cancers. UGT1A1 mRNA was also decreased in breast tumors as compared to normal breast tissues from both African American and European American women. We postulated that the decreased levels of UGT1A1 mRNA in breast cancers may be due to a genetic variant in the promoter of UGT1A1. In all UGT1A1 genotypes observed in our study, the mean UGT1A1 mRNA expression levels was significantly decreased among breast cancer cases as compared to controls (p = 0.04). Our research findings suggest that further investigations are necessary to determine the role of UGT1A1 in breast carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4120. doi:1538-7445.AM2012-4120