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

Athena Starlard Davenport

doi:10.4172/2157-7609.s4-001

Abstract

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.

Highlights

Breast cancer is the most common malignancy in women in the United States [1]
UGT1A4 (p = 0.007) and UGT2B7 mRNA expression (p = 0.001) both showed a similar decrease in mRNA expression pattern as UGT1A1 in breast tumor specimens; the mean mRNA levels of UGT1A1 was most significantly decreased in breast cancers compared to normal controls (p = 0.0006) compared to UGT1A4 (p = 0.0068) and UGT2B7 (p = 0.0014)
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

Summary

Introduction

Breast cancer is the most common malignancy in women in the United States [1]. Despite recent advancements in breast cancer research, including breast cancer staging as a prognostic marker, it is still difficult to predict optimal therapy, breast cancer recurrence, and Starlard-Davenport et al.clinical outcome [2,3,4]. A major risk factor for breast cancer development in women is association with exposure to increased concentrations of estrogens over a prolonged period of time [5]. 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 [14,15,16]. 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 [17,18,19,20]. The frequency of TA repeats has been reported to vary among different ethnic groups [20] and ER status [18]

Objectives

Methods

Results

Conclusion