J. Steroid Biochem. Molec. Biol. Vol. 37, No. 3, pp. 305-316, 1990 0960-0760/90 $3.00 + 0.00 Printed in Great Britain. All rights reserved Copyright © 1990 Pergamon Press pie Plenary Lectures REGULATION OF PROLIFERATION, INVASION AND GROWTH FACTOR SYNTHESIS IN BREAST CANCER BY STEROIDS ROBERT B. DICKSON, ERIK W. THOMPSON and MARC E. LIPPMAN Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, 3800 Reservoir Rd, NW Washington, DC 20007, U.S.A. Summary--Endogenous ovarian estrogens and progestins appear to play a critical role in the development and progression of breast cancer. Local productions of growth factors probably also contribute to malignant proliferation, while production and activation of collagenolytic enzymes may be equally critical for local invasive processes. The current review focusses on characterization of growth factor-receptor systems operant in normal and malignant breast epithelium. In addition, the determinants of local invasion are reviewed:attachment, modality, and proteose secretion. Finally, data are discussed concerning the regulation of both proliferation and invasion by hormones and antihormonal agents in hormone-dependent breast cancer. The results suggest new potential pharmacologic targets to explore to suppress onset and progression of breast cancer. INTRODUCTION: HORMONE-RESPONSIVE BREAST CANCER MODELS Exposure to the hormonal estrogenic steroids appears to be a critical in the carcinogenesis phase of human breast cancer, and in mitogen- esis of the hormone-dependent form of the disease. The initial hormonal requirements are often bypassed with progression of breast can- cer to a more advanced disease. Advanced disease also involves basement membrane inva- sion and distant metastases of the tumor. For experimental studies, established human breast cancer cell lines, generally derived from pleural effusions[l], can be used to study both the estrogen-dependent and -independent forms of the disease. The estrogen receptor positive MCF-7 cell line [2] has been widely studied (along with a few other such lines: T47D, ZR75- 1) and provides a useful system to evaluate the molecular basis for action of estrogen and other hormones in breast cancer. This cell line exhibits estrogen sensitivity for progesterone receptor expression [3], proliferation in vitro [4-6], base- ment membrane invasion in vitro [7, 8], and expression of a host of specific mRNA species and proteins [9-16]. Of particular note, MCF-7 Proceedings of the XIV Meeting of the International Study Group for Steroid Hormones, Rome, Italy, 30 November-2 December 1989. tumor formation in the nude mouse is depen- dent upon administration of estrogen[17]. Recent progress indicates that a number of polypeptide growth factors regulate breast cancer cell growth in vitro, and may contribute to the proliferative effects of estrogen on MCF-7 cells through autocrine and paracrine actions. In this review, we summarize our current under- standing of the regulation of breast cancer cell proliferation and invasiveness by estrogenic hormones, antiestrogenic antagonists and growth factors. ANTIESTROGENS IN VITRO AND IN VIVO Antiestrogens have been extensively and suc- cessfully used in the clinical treatment of breast cancer; and they are also useful agents for in vitro study of breast cancer cell lines. The substituted triphenylethylene tamoxifen, and its active 4-hydroxylated metabolite (OHT), dis- play both estrogen agonism and antagonism in various systems[18-32]. They have relative binding affinities (RBAs) for rat uterine estro- gen receptor in vitro of approximately 2 and 200% of 17~-estradiol, but exhibit nearly equal activity in vivo with a minimum effective dose of 0.05--0.1 mg/kg [33]. Partial estrogen agonistic activity of these triphenylethylene compounds 305