Estrogens, Microtubules, and Aneuploidy: Mechanisms of Mammary Gland Tumorigenesis

摘要

The role of estradiol (E2) metabolism in mammary carcinogenesis was studied in a rat model. Two strains were employed: the ACI is extremely sensitive to E2 carcinogenicity, whereas the Sprague-Dawley is resistant. Characterization of E2 metabolism in liver microsomal prepartions showed robust metabolism at substrate concentrations form 60phiM to 3nM. The latter value approximates the physiological concentration of E2. In the micromolar range both strains produce estrone and 2-hydroxy-E2. In the nanomolar range, however, estrone is the dominant product from the Sprague-Dawley whereas the ACI makes almost entirely 4-hydroxy-E2. Given that 4-hydroxy-E2 may be the key carcinogenic metabolites of E2, this strain-specific metabolism may explain the noted difference in E2 carcinogenicity between the two strains. Profiling of cytochrome P45O enzymes (CYPs) in the livers of the two strains by Western analysis did not show significant differences. Particularly noteworthy was the absence of CYPlBl, the purported estrogen 4-hydroxylase. Although liver determines the systemic fate of E2, metabolism and effects of E2 in target tissues are of even more concern. We tried to extend these studies into a rat mammary epithelial cell (RMEC) system. We isolated RMEC from both rat strains, but the result cultures were mixed population containing both myoepithelial and luminal epithelial cells. Minimal metabolic activity was seen, and the viability of these cultures was poor, preventing the continuation of these studies.