Control of proliferation in the normal and neoplastic breast

I. INTRODUCTION Understanding the factors regulating normal human breast epithelial growth and development is not only academic, since the factors involved in normal proliferative activity also have roles in the development and progression of malignant breast tumors (Anderson et al., 1998). Since there is no breast development in the absence of functional ovaries and the premature loss of ovarian function greatly reduces breast cancer risk, it is clear that the ovarian steroids are necessary factors for both normal and abnormal processes (Key and Pike, 1988; Laron et al., 1989). The steroids synthesized and secreted by the ovary from puberty onward are estradiol and progesterone. Estradiol and progesterone regulate mammary gland development at puberty and pregnancy and are important hormones in the initiation, promotion, and progression of breast cancer. Epidemiological and other evidence indicates that a woman’s reproductive history is related to the risk of developing breast cancer. Decreased exposure to steroid hormones because of a late menarche or an early menopause provides a protective effect against breast cancer, suggesting that the assumed reduced proliferative activity during menstrual cycles may help to prevent breast cancer (Cohen and Ellwein, 1990; Cohen and Ellwein, 1991; Pike et al., 1993). It has been known for over a century that the ovarian secretions can promote breast tumor growth, and it was over 30 years ago that the cellular receptor for estrogen was described (Schinzinger, 1889; Beatson, 1896; Toft and Gorski, 1966; Jensen et al., 1968). The presence in breast tumors of the cellular receptors for both estrogen and progesterone was later observed to correlate with the effectiveness of endocrine therapies such as antiestrogen treatment, thus indicating the importance of estrogens in tumor growth (McGuire and Clark, 1983; Sunderland and McGuire, 1991). Pioneering studies on breast cancer cells in vitro confirmed that local growth factors were responsible at the local level for estrogen-induced growth 74 CLARKE ET AL.