In vitro biotransformation of estradiol by explant cultures of murine mammary tissues

Summary In vivo experiments have demonstrated a correlation between the extent of 16-hydroxylation of estradiol and incidence of mammary cancer. The ability of mammary ductal epithelium (MDE), the site for neoplastic transformation, to metabolize estradiol or to accumulate estradiol metabolites has not been unequivocally established. Using a newly developed mammary explant culture system and a radiometric assay, we have compared the site-specific metabolism of estradiol (E₂) by the C-17-oxidation and C-16-hydroxylation pathways in mouse tissues that differ in relative risk for mammary cancer. A comparison between MDE (target tissue) and liver (nontarget tissue) from NFS (low risk) and C3H/ouj (high risk) mice revealed that: a) increase in C-17-oxidation was similar in MDE and liver from the two strains, and b) while C-16-hydroxylation was similar in liver from the two strains (p = 0.5, n.s.), it was increased 4-fold in the MDE from the high risk C3H/ouj strain relative to that from the low risk NFS strain (p = 0.001). Furthermore,in vivo administration of progesterone resulted in modulation of cell proliferation as well as of E2 metabolism in mammary explant cultures. The effect of progesterone depended upon the presence of the MtV-2 proviral gene. This study demonstrates that mammary explants can extrahepatically metabolize estradiol. The specific risk-related increase in C-16-hydroxylation suggests that intrinsic metabolic ability of the target tissue leading to the formation of 16-hydroxyestrone from estradiol may be a determinant in the relative risk for developing mammary cancer.Abbreviations MMTV Mouse Mammary Tumor Virus - E₁ estrone - 2-OHE₁ 2-hydroxyestrone - 16-OHE₁ 16-hydroxyestrone - MDE Mammary Ductal Epithelium - HN Hyperplastic Nodule - MtV-2 Proviral Gene of Mammary Tumor Virus - GRS^MtV-2+ GRS strain of mouse carrying MtV-2 proviral gene - GRS^MtV-2- GRS strain of mouse lacking MtV-2 proviral gene - 020^MtV-2- 020 strain of mouse lacking MtV-2 proviral gene - 020^MtV-2+ 020 strain of mouse carrying MtV-2 proviral gene