Vol. 50, Issue 2, 151-196, June 1998

Basic Guide to the Mechanisms of Antiestrogen Action

Jennifer I. Macgregor and V. Craig Jordan^a

Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois

I. Introduction
II. Unresolved Issues in 1984
    A. Species Differences
    B. Differences Between Antiestrogens In Vivo and In Vitro
    C. Antiestrogen Binding Sites
III. The Estrogen Receptor
IV. A Second Receptor
V. Estrogen Receptor
    A. Receptor Functions
    B. Estrogen Action
VI. Estrogen Receptor Regulation
    A. Estrogen Withdrawal
    B. Receptor Regulation
    C. Loss of the Receptor
VII. Antiestrogen Classification
    A. Type I
    B. Type II
VIII. Mechanisms of Antiestrogen Action
    A. Receptor Mutation and Antiestrogens
    B. Interactions with Estrogen Response Elements
IX. Antiestrogens and the Cell Cycle
X. Antiestrogens and Growth Factors
    A. Transforming Growth Factor
    B. Transforming Growth Factor
    C. Insulin-Like Growth Factor
XI. Clinical Value of Tamoxifen
    A. Contralateral Breast Cancer
    B. Endocrine Function and Tamoxifen
    C. Tamoxifen and Bone
    D. Tamoxifen and Lipids
XII. Complexity of Antiestrogen Action
    A. Estrogen Receptor-Associated Proteins
    B. Antiestrogen Response Elements
XIII. Concerns with Tamoxifen
    A. Uterine Carcinogenesis
    B. Rat Liver Carcinogenesis
    C. Mechanism of Carcinogenesis
    D. Tamoxifen Metabolism
XIV. Drug Resistance Mechanisms
    A. Metabolic Activation
    B. Mutant Receptors
    C. Alternate Pathways
XV. Clinical Application of New Antiestrogens
    A. Tamoxifen Analogs for Breast Cancer
    B. Pure Antiestrogens for Breast Cancer
    C. Targeted Antiestrogens for Osteoporosis
        1. Raloxifene (also referred to in the literature as LY 156, 758, keoxifene, LY 139, 481-HCL, Evista®).
        2. Droloxifene.
        3. Idoxifene.
XVI. New Compounds and New Opportunities
    A. EM-800
    B. Peripheral Selectivity
XVII. Crystallization of the Raloxifene-Estrogen Receptor Complex
XVIII. Summary and Conclusions
Acknowledgments
References