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

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.

Keywords: Breast cancer; Genetic polymorphism; UGT1A1; UGTs.

Figure 1:. mRNA expression of UGTs in human breast samples relative to B-actin.

Quantitative real-time PCR analysis of UGT1A1, UGT1A4, UGT1A10, and UGT2B7 mRNA expression in normal and tumor breast tissues. Solid horizontal lines demonstrate the mean with the 95% CI of each individual group. All data are shown as the ratio between the UGT target gene and B-actin internal control on a logarithmic scale. p -value, nonparametric, Mann-Whitney tests. *p<0.05, **p <0.01 is statistically significant.

Figure 2:. Effect of UGT1A1 mRNA expression in human breast samples on ethnicity, menopausal status, and stage of breast disease.

Quantitative real-time PCR analysis of UGT1A1 mRNA expression in normal (N) and tumor (T) human breast tissues and its effect on ethnicity (A), menopausal status (B), and stage of breast disease (C). Solid horizontal lines demonstrate the mean with the 95% CI of each individual group. All data are shown as the ratio between the UGT target gene and B-actin internal control on a logarithmic scale. p -value, nonparametric, Mann-Whitney or Kruskall-Wallis tests. *p < 0.05 is statistically significant.