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

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Summary

In vivo experiments have demonstrated a correlation between the extent of 16α-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-16α-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-16α-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-16α-hydroxylation suggests that intrinsic metabolic ability of the target tissue leading to the formation of 16α-hydroxyestrone from estradiol may be a determinant in the relative risk for developing mammary cancer.

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Abbreviations

MMTV:

Mouse Mammary Tumor Virus

E1 :

estrone

2-OHE1 :

2-hydroxyestrone

16α-OHE1 :

16α-hydroxyestrone

MDE:

Mammary Ductal Epithelium

HN:

Hyperplastic Nodule

MtV-2:

Proviral Gene of Mammary Tumor Virus

GRSMtV-2+ :

GRS strain of mouse carrying MtV-2 proviral gene

GRSMtV-2- :

GRS strain of mouse lacking MtV-2 proviral gene

020MtV-2- :

020 strain of mouse lacking MtV-2 proviral gene

020MtV-2+ :

020 strain of mouse carrying MtV-2 proviral gene

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Authors and Affiliations

  1. Breast Cancer Research Laboratory, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, 10021, New York, NY, USA

    Nitin T. Telang, Hiroaki Kurihara & Michael P. Osborne

  2. Laboratory of Biochemical Endocrinology, The Rockefeller University, 10021, New York, NY, USA

    H. Leon Bradlow

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  1. Nitin T. Telang
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  2. H. Leon Bradlow
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  3. Hiroaki Kurihara
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  4. Michael P. Osborne
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Telang, N.T., Bradlow, H.L., Kurihara, H. et al. In vitro biotransformation of estradiol by explant cultures of murine mammary tissues. Breast Cancer Res Tr 13, 173–181 (1989). https://doi.org/10.1007/BF01806529

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