1.4 Human Breast Biology
1.4.2 Development of the Human Mammary Gland
Mammary gland development is probably one of the most fascinating and puzzling biological phenomena. The most important element in this puzzle is the fact that the mammary gland seems to be only organ that is not fully developed at birth (Vorher et al., 1974). No other organ presents such dramatic changes in size, shape and function as does the breast during growth, puberty, pregnancy and lactation (Fig. 1.19).
Figure 1.19: Development Stages of the Mammary Gland
The structure of the mammary gland is dependent on the development stage. The adult female mammary gland experiences recurrent cycles of regulated growth, differentiation and apoptosis. Estrogen and progesterone play a central role in this process. The cycles that occur in the mammary gland can be divided into several stages: puberty, pregnancy, lactation and involution. Each stage can be further described by the structure of the glands, called lobules or lobes (Russo and Russo, 1998).
1.4.2.1 Prenatal
The structure of the mammary gland is essentially similar in both sexes until puberty. The first visible indication of mammary gland development can be found during day 35 of pregnancy (Dawson, 1934) with the proliferation of paired areas of epithelial cells in the epidermis of the thoracic region. During week 5, these areas of proliferation have extended in a line between the foetal axilla and inguinal region and form two indistinct ridges called the mammary ridges or milk lines (Dawson, 1934; Dabelow, 1957). By the end of the week 6, the mammary ridges have regressed back in to two areas in the thoracic region, where two solid epithelial masses begin to grow downwards into the underlying mesenchyme. During week 10, solid secondary epithelial buds grow and branch off the main mammary bud, establishing the future lobed structure of the mature gland. In the epidermis overlying the developing gland, the nipple begins to form. During the same period, the mesenchymal cells differentiate to form fibroblasts, smooth muscle cells,
capillary endothelial cells and adipocytes. Around week 20 the solid mammary sprouts canalise and the epidermis in the region of the nipple becomes depressed, forming the mammary pit. The epithelial cells lining the ductules first appear as a biolayer of cuboidal cells. The luminal layer rapidly gains the characteristic of secretory cells while the basal layer becomes myoepithelial. By six months, the basic tubular architecture of the gland has become established. The tubules are separated by "fat islands" within a dense fibroconnective tissue stroma and rudimentary secretory epithelial cells have become functional.
Perinatally the gland can exist as primitive ducts with solid end buds, through ducts with bud like projections, to ducts with budding primitive alveoli. Postnatally maternal hormones may cause a transient secretory activity in the rudimentary breast (Hiba et al., 1977). The secretory activity of the newborn gland subsides 3-4 weeks postnatally. During the same period, the nipple is formed by proliferation of the the underlying mesenchyme, causing inversion of the embryonic mammary pit. The glands normally remain at this rudimentary stage until puberty.
1.4.2.2 Puberty
The changing hormonal environment at the onset of puberty is the controlling factory for the sexually dimorphic growth and development of the mammary gland. In the male, testosterone acts on the mesenchymal cells to inhibit further growth of the mammary gland. In the female, estrogen acts on the mesenchymal cells to stimulate further development. The gland increases in size, mainly due to the deposition of interlobular fat. The ducts extend and branch into the expanding stroma. The accompanying epithelial cell proliferation and basement membrane remodeling is controlled by interactions between the epithelium and the intralobular hormone sensitive zone of fibroblasts. By adulthood the complete ductal architecture of the glands has been established.
The mammary glands remain in this mature but inactive state until pregnancy, which brings about the next major change in the hormonal environment. However, there are relatively small cyclical changes brought about by ovarian hormones released during the menstrual cycle. During the follicular phase, the stroma is less dense, the epithelial cells of the smaller ducts are cuboidal, there is no secretion and early in the follicular phase the duct lumens are not apparent. During the luteal phase, epithelial cells become more columnar, the lumens open up and there is some secretion. There is a moderate level of cell proliferation, increasing to a maximum towards the end of the luteal phase. This followed by abrupt involution and apoptosis during the last few days, before the onset of menstruation.
1.4.2.3 Pregnancy and Lactation
During pregnancy, the mammary gland attains its maximum development. This occurs in response to hormones initially from the corpus luteum (estrogen and progesterone), followed by placental hormones (estrogen, progesterone and somatotropin), pituitary hormones (prolactin) and adrenocorticoids from the adrenal gland. Estrogen exerts its effects mainly on the ductal system, while progesterone promotes alveolar development. This occurs in two distinctly dominant phases characteristic of early and late stages of pregnancy (Dabelow, 1957; Salazar and Trobon, 1974; Vorherr, 1987). During the first trimester, the terminal ductules branch and
elongate. The epithelial cells proliferate from stem cells distributed throughout the gland. During the second trimester, differentiation of alveoli from terminal end buds predominates. The alveoli possess two layers of cells, the luminal cells are the prospective secretory cells, while the basal cells are myoepithelial and extend contractile processes in a network around the alveolus. There are low levels of secretion from cells in the ductules and more mature alveoli. During the third trimester, the alveoli mature. The epithelial cells become cuboidal, with an extensive basal endoplasmic reticulum, basally situated nuclei, apical granules and cytoplasmic lipid droplets.
The functional gland architecture is maintained by prolactin, released from the anterior pituitary in response to a suckling stimulus from the infant.
Lactation ceases at the end of the suckling period. Epithelial cells numbers are reduced through apoptosis, the remaining cells become inactive and reduced in size and alveoli and ducts regress back to a resting state. The stromal fibroblasts reconstruct the collagenous interlobular connective tissue and the gland becomes reinvaded with adipose tissue. Though the post lactational breast returns to a resting state, the architecture of the gland and composition of the supporting tissues are not identical to their structures before pregnancy.
1.4.2.4 Menopause
The resting state is maintained in a manner similar to that of the post-pubertal gland, with the potential to re-enter the fully functional state during subsequent pregnancies. The amount of elastic tissue increases, the stroma becomes more fibrous and less cellular and adipose tissue is lost. The levels of circulating ovarian hormones falls, the ductal elements degenerate and dense connective tissue replaces the intralobular loose connective tissue.
1.5 CANCER