4479

It is well established that increased levels of estrogens circulating in the serum and estrogen-targeted cells such as breast cells have a significant impact on breast cancer risk. The local concentration of estrogen in human breast cells is the result of a balance between estrogen synthesis and metabolism. Recently, we have shown that UDP-glucuronosyltransferases (UGTs) are involved in the inactivation of estrogens and facilitate the removal of these compounds from the body potentially preventing accumulation of estrogens in estrogen target cells and tissues. Specifically, human UGT1A10 catalyzes the glucuronidation of all native and hydroxylated estrogens. Here, we show for the first time that treatment of MCF7 (ER-positive) breast cancer cells with estradiol produces a dose-dependent upregulation of mRNA levels for this isoform, followed by a corresponding steady decrease, and that this upregulation can be blocked by the ER-antagonist, ICI182,780. In contrast, estradiol causes a significant decrease of UGT1A10 mRNA in MCF10F non-tumorigenic breast cells and has no effect on MDA-MB-231 (ER-negative) breast cancer cells. Collectively, these results suggest that the induction of UGT1A10 mRNA expression by estradiol is mediated through the ER. We have also characterized UGT1A10 mRNA in a total of 61 normal and malignant human breast tissue samples in from African American and Caucasian women by quantitative real-time PCR analysis in order to further characterize the role of this isoform in estrogen target tissue. Although, these results show wide individual variation in the expression of UGT1A10 mRNA within the normal and malignant tissue samples, the mean expression levels were significantly higher in normal tissues as compared to cancer tissues (252 ± 86 vs. 68.1 ± 25.6, for normal and malignant tissue, respectively; p<0.05). The findings from this study suggest that UGT1A10 could have a significant impact on controlling the availability of estradiol for ER, thereby protecting breast cells from the potential carcinogenic effects of estrogens. (Supported by DK60109 and GM075893 to AR-P, and minority supplement to AS-D).

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA