The Molecular Biology of RU486. Is There a Role for Antiprogestins in the Treatment of Breast Cancer?*

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Abstract
I. Introduction ENDOCRINE therapy used either prophylactically or therapeutically for the treatment of locally advanced or metastatic breast cancers offers many advantages to patients whose tumors contain functional estrogen and progesterone receptors (ER and PR). The range of treatments defined as endocrine include surgical ablation of endocrine glands, administration of pharmacological doses of steroid hormones, chemical blockade of steroid hormone biosynthesis, and inhibition of endogenous steroid hormone action at the tumor with synthetic antagonists. The last of these approaches is the most widely used, making the antiestrogen tamoxifen the preferred first-line therapeutic agent for treatment of hormone-dependent metastatic breast cancer. The wide-spread use of tamoxifen reflects its efficacy and low toxicity, and the fact that it makes good physiological sense to block the local proliferative effects of estrogens directly at the breast. But are estrogens the only hormones with a proliferative impact on the breast and on breast cancers? This review focuses on evidence that progesterone also has proliferative actions in the breast; on the role of synthetic progestins in breast cancer treatment; on the molecular biology of progesterone antagonists; and on the preliminary data showing that progesterone antagonists may be powerful new tools for the management of metastatic breast cancer, because they block the local effects of endogenous progesterone on breast cell proliferation. The reader is also referred to the excellent general review on progestin regulation of cell proliferation by Clarke and Sutherland (1). The structures of the agonists and antagonists discussed in this review are shown in Fig. 1.

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