Introduction
The breasts, or mammary glands, of mammals are important for the survival of the newborn and thus of the species. Nursing of the young in the animal kingdom has many physiologic advantages for the mother, such as aiding postpartum uterine involution, and for the neonate, in terms of the transfer of immunity and bonding. In humans, social influences have reduced the prevalence of breast-feeding of neonates and may have interfered with its physiologic role. It has become increasingly apparent that the advantages of nursing are substantial for both mother and child.

An understanding of the morphology and physiology of the breast and the many endocrine interrelationships of both is essential to the study of the pathophysiology of the breast and the management of benign, preneoplastic, and neoplastic disorders.

Embryology
During the fifth week of human fetal development, the ectodermal primitive milk streak, or “galactic band,” develops from axilla to groin on the embryonic trunk. In the region of the thorax, the band develops to form a mammary ridge, whereas the remaining galactic band regresses. Incomplete regression or dispersion of the primitive galactic band leads to accessory mammary tissues, found in 2% to 6% of women.

At 7 to 8 weeks’ gestation, a thickening occurs in the mammary anlage (milk hill stage), followed by invagination into the chest wall mesenchyme (disc stage) and tridimensional growth (globular stage). Further invasion of the chest wall mesenchyme results in a flattening of the ridge (cone stage) at 10 to 14 weeks’ gestation. Between 12 and 16 weeks’ gestation, mesenchymal cells differentiate into the smooth muscle of the nipple and areola.

Epithelial buds develop (budding stage) and then branch to form 15 to 25 strips of epithelium (branching stage) at 16 weeks’ gestation; these strips represent the future secretory alveoli. The secondary mammary anlage then develops, with differentiation of the hair follicle, sebaceous gland, and sweat gland elements, but only the sweat glands develop fully at this time. Phylogenetically, the breast parenchyma is believed to develop from sweat gland tissue. In addition, special apocrine glands develop to form the Montgomery glands around the nipple. The developments described thus far are independent of hormonal influences.

During the third trimester of pregnancy, placental sex hormones enter the fetal circulation and induce canalization of the branched epithelial tissues (canalization stage). This process continues from the twentieth to the thirty-second week of gestation. At approximately term, 15 to 25 mammary ducts are formed, with coalescence of duct and sebaceous glands near the epidermis. Parenchymal differentiation occurs at 32 to 40 weeks with the development of lobuloalveolar structures that contain colostrum (end-vesicle stage). A fourfold increase in mammary gland mass occurs at this time, and the nipple-areolar complex develops and becomes pigmented. In the neonate, the stimulated mammary tissue secretes colostral milk (sometimes called witch’s milk), which can be expressed from the nipple for 4 to 7 days postpartum in most neonates of either sex. In the newborn, colostral secretion declines over a 3- to 4-week period, owing to involution of the breast after withdrawal of placental hormones. During early childhood, the end vesicles become further canalized and develop into ductal structures by additional growth and branching.

Molecular Biology of Mammary Gland Development
Normal development of the mammalian breast depends on a combination of systemic mammotrophic hormones and local cell–cell interactions. The local cellular interactions appear to be mediated by a variety of growth factors, some of which belong to the epidermal growth factor, transforming growth factor beta (TGF-b), fibroblast growth factor (FGF), and Wnt gene families. Some of these growth regulators have been shown to affect mammary cell growth and differentiation in experimental systems, whereas their differential expression in the developing breast suggests that they may act in concert with systemic hormones during normal glandular development. Systemic hormonal alterations also combine with local cellular effects to promote involution of the mammary gland after lactation.

TGF-a a member of the epidermal growth factor family, may play a role in both ductal growth and alveolar development of the mammary gland. Ectopic expression of TGF-a causes significant alterations in mammary epithelial growth and differentiation in transgenic mice and other systems, and the in vivo localization of TGF-a to actively growing end buds of the mouse mammary gland is consistent with a role in normal ductal development. In addition, the changing temporal and spatial expression pattern of TGF-a in the breast during pregnancy suggests that it may function in mediating lobuloalveolar development. TGF-a is up-regulated in both mammary ductal epithelium and stromal fibroblasts during rat and human pregnancy. It is therefore possible that TGF-a functions as an autocrine or paracrine intermediate in directing hormonally induced mammary morphogenesis.

Studies of the growth factors FGF-1 and FGF-2 in the mouse have suggested that they function in promoting mammary ductal development during sexual maturity. At the onset of ovarian function, FGF-1 expression is up-regulated in ductal epithelium and may provide an autocrine growth stimulus for the proliferating breast. In contrast, FGF-2 is expressed in the mammary stroma, in which it may act indirectly as a ductal morphogen through its influence on extracellular matrix composition. FGF-1 and FGF-2 are well-known angiogenic factors and may also contribute to early breast development by stimulating neovascularization during ductal growth.

The principal members of the TGF-b family—TGF-b 1, -b2, and -b3—appear to be involved in ductal morphogenesis of the virgin mouse mammary gland and in regulating the onset of lactation. TGF-b may govern early ductal development by maintaining an open ductal branching pattern that is required for subsequent alveolar development. Maintenance of this ductal architecture requires suppression of lateral bud growth, and TGF-b inhibits ductal growth both in vitro and in transgenic mice, possibly through its effects on extracellular matrix deposition. In addition, the TGF-b family may play a role in inhibition of lactation. TGF-b expression levels are down-regulated during lactation, and milk production is impaired in TGF-b transgenic mice.

Several members of the Wnt gene family of secreted glycoproteins are xpressed in the developing mouse mammary gland and may play a role in its normal development. The first characterized member of this family, Wnt-1, was initially identified as an oncogene in mouse mammary tumor virus–induced mammary tumors and induces mammary hyperplasia when expressed in the mammary glands of transgenic mice. Although Wnt-1 is not expressed during normal mammary development, at least six other members of the Wnt family are differentially expressed in the mouse mammary gland during early development, pregnancy, and lactation. Because some of these genes can mimic the effects of Wnt-1 in mammary cell lines, it seems likely that they influence growth or differentiation in vivo. The spatial expression patterns of these Wnt genes have not yet been reported, with the exception of Wnt-2. That expression of this gene during early mammary development has been localized to the growing epithelial end buds suggests that it may be involved in early ductal morphogenesis.

The postlactational breast requires a combination of lactogenic hormone deprivation and local signals to undergo glandular involution. The process of involution is characterized by apoptotic cell death and tissue remodeling. Certain gene products associated with apoptosis are up-regulated during mammary involution; however, the factors that trigger the cell death pathway have not been clearly defined. Local extracellular proteases involved in tissue remodeling are up-regulated during breast regression, and this may result in part from the action of TGF-a 1 in the postlactational gland.

The regulated expression of locally acting growth factors in the developing breast acts in combination with circulating hormones to control mammary growth, differentiation, and regression. Further investigation of the function of ligands in vivo will undoubtedly have importance for the understanding of both breast development and mammary tumorigenesis.

M. P. Osborne: Department of Surgery, Joan and Sanford I. Weill Medical College, Cornell University
New York Presbyterian Hospital, New York, New York

References