This chapter—which raises more questions than it answers—defines an agenda for the basic research in biology that will be required to fully understand the relationship between oral contraceptives and breast cancer.

SIGNAL COMPLEXITY IN BREAST REGULATION

The complexity of regulation of breast physiology may exceed that of any other hormonal target tissue (Table 3-1). The effects of both classical hormones and a variety of growth hormones on growth and function of breast tissue and cells have been extensively studied. Classical hormones cause growth, differentiation, and milk synthesis and secretion, and include hormones from the anterior pituitary (prolactin, growth hormone), ovary (estrogen, progesterone, relaxin), placenta (placental lactogen[s], growth hormone), adrenal cortex, thyroid, and pancreas. These hormones may act directly on specific pathways of metabolism and cell division within the breast, or they may work indirectly through locally secreted growth factors (see below), which, in turn, regulate cell function. Additionally, the hormones and growth factors may interact with and modify each other's effects, changing secretion rates and actions (e.g., estrogens increasing prolactin secretion and tissue receptors for progesterone).

Growth hormones or factors are peptides secreted by most, if not all, cells. They are essential for growth and differentiation of many tissues. Unlike the classical hormones, these substances were discovered only after it was noted that many cells in culture in chemically defined media were incapable of growth, cell division, or differentiation without the addition of serum from animals. Growth factors can act as local growth regulators and can inhibit or stimulate mitogenesis of epithelial or stromal cells; they can also stimulate angiogenesis and influence cell transformation and immortalization.

In culture, normal or malignant breast tissue can secrete transforming growth factors (TGF-α) or (TGF-β), epidermal growth factor (EGF), insulin-like growth factors (IGF-I and IGF-II), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) under various conditions. These factors can act as paracrine and autocrine growth regulators. TGF-β has been shown to act normally as an inhibitor of mammary gland growth, whereas EGF acts as a stimulator of mammary growth (Lippman and Dickson, 1989).

Recent work suggests that hormones (e.g., estrogen) may in some cases act by changing growth factor secretion locally, and perhaps by changing receptors for these factors as well. The observation that estrogen receptors in stromal tissue may be responsible for differen-



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