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Evidence for the Hormone Dependency of Hepatic Hyperplastic Nodules: Inhibition of Malignant Transformation After Exogenous 17β-Estradiol and Tamoxifen

Authors

  • Shaindel Y. Mishkin,

    1. Department of Medicine, Royal Victoria Hospital and McGill University Clinic and Department of Pathology, University of Toronto, Ontario Canada H3A 1A1
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    • Dr. Mishkin is the recipient of a Chercheur Boursier Award from the Quebec Medical Council (FRSQ).

  • Emmanuel Farber,

    1. Department of Medicine, Royal Victoria Hospital and McGill University Clinic and Department of Pathology, University of Toronto, Ontario Canada H3A 1A1
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  • Ru Kun Ho,

    1. Department of Medicine, Royal Victoria Hospital and McGill University Clinic and Department of Pathology, University of Toronto, Ontario Canada H3A 1A1
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  • Shree Mulay,

    1. Department of Medicine, Royal Victoria Hospital and McGill University Clinic and Department of Pathology, University of Toronto, Ontario Canada H3A 1A1
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  • Seymour Mishkin

    Corresponding author
    1. Department of Medicine, Royal Victoria Hospital and McGill University Clinic and Department of Pathology, University of Toronto, Ontario Canada H3A 1A1
    Current affiliation:
    1. Department of Pathology, Guangxi Medical College, Guanxi, China
    • Seymour Mishkin, M.D., F.R.C.P., Department of Medicine, Royal Victoria Hospital, 687 Avenue des Pines Ouest, Montreal, Quebec, Canada H3A 1A1.
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  • This work was also presented in part at the Annual Meeting of the Canadian Society for Clinical Investigation (CSCI), September, 1981, Toronto, Ontario, Canada (Clin. Invest Med. 1981; 4:14B) and at the Annual Meeting of the American Association for Cancer Research, St. Louis, Missouri, April, 1982 (Proc. Am. Assoc. Cancer Res. 1982; 23:192).

  • This work is dedicated to the memory of Moe Yalovsky

Abstract

Hepatic hyperplastic nodules (HHNs) in rats were studied as an experimental prototype of oral contraceptive-related hepatic tumors. We have found cytoplasmic estrogen receptors in HHNs produced by acetylaminofluorene (AAF) (four cycles of 0.02% in diet). Rats with AAF-induced HHNs were randomized into four groups: (i) AAF-treated control; (ii) estrogen alone (estradiol-17β); (iii) tamoxifen alone, and (iv) estrogen + tamoxifen. After 8 months of treatment with estrogen (estradiol-17β) in combination with tamoxifen, there was regression of nodular involvement and no evidence of malignant transformation. Decreased nodular proliferation also occurred after 2 and 4 months treatment with estradiol-17β and after 8 months of tamoxifen administration. The incidence of hepatocellular carcinoma after 8 months of treatment was significantly less after treatment with estrogen (40%) or tamoxifen (42.9%) when compared to AAF-treated controls (87.5%). The number of -γ-glutamyitranspeptidase-positive foci were reduced in all treatment groups after 2,4, and 8 months of treatment; these changes were most pronounced in the estrogen-treated group and did not directly correlate with the per cent inhibition of malignant transformation. Our results suggest that the malignant transformation of estrogen receptor-positive HHNs is hormone dependent.

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