The following briefly describes the structure and development of the mammary gland from it's embryologic inception to postmenopausal involution. The description deals with human mammary gland development, though much of the experimental data has been generated using the mouse mammary gland as a model. The mammary gland has many advantages for the study of branching morphogenesis in that the majority of growth and development occurs post pubertally under hormonal regulation and the organ is relatively accessible for experimental manipulation.
The mammary gland is a structurally dynamic organ, varying with age, menstrual cycle and reproductive status. It is a branched tubuloalveolar gland. Secretory acinii are grouped within lobules and drain into intralobular ducts which in turn drain into interlobular ducts. The lobules are organised into 15 to 20 lobes, each of which empty into separate lactiferous sinuses and from there into lactiferous ducts which open onto the nipple. The stroma of the gland consists of a dense interlobular connective tissue, within which are varying amounts of adipose tissue. Fibrous suspensory ligaments provide some internal support. The intralobular stroma consists of a cellular loose connective tissue with a zone of hormone sensitive fibroblasts surrrounding the lobular epithelial components. These are thought to take part in epithelial/basement membrane/stromal inductive interactions during morphogenesis and differentiation.
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, with the proliferation of paired areas of epithelial cells in the epidermis of the thoracic region. Two days later, these areas of proliferation have extended in a line between the fetal axilla and inguinal region and form two indistinct ridges called the mammary ridges or milk lines.
By the end of week 6, the mammary ridges have regressed back to two areas in the thoracic region, where two solid epithelial masses (the mammary buds) begin to grow downwards into the underlying mesenchyme. This solid core of cells continues to evaginate into the underlying stroma and becomes surrounded by a more cellular zone of fibroblast like cells within a dense collagenous 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 cannalize 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 bilayer of cuboidal cells. The luminal layer rapidly gains the characteristics of secretory cells, while the basal layer becomes myoepithelial. By six months, the basic tubular architechture of the gland has become established. The tubules are separated by "fat islands" within a dense fibroconnective tissue stroma and the rudimentary secretory epithelial cells have become functional.
The extent of gland development at birth is highly variable and is thought to depend on the levels of maternal oestrogens. Perinatally the gland can exist as primitive ducts with solid end buds, through ducts with bud like projections, to ducts with budding primitive alveoli. During the first few days post natally, maternal hormones may cause a transient secretory activity in the rudimentary breast. Additionally some post natal secretory development of the epithelial cells may occur, with areas of localised hyperplasia and a more apocrine secretion. This can be detectable for up to two months postnatally. During the same period, the nipple is formed by proliferation of the underlying mesenchyme, causing evertion of the embryonic mammary pit. The glands normally remain at this rudimentary stage until puberty.
The changing hormonal environment at the onset of puberty is the controlling factor 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, oestrogen 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 remodelling is controlled by interactions between the epithelium and the intralobular hormone sensitive zone of fibroblasts. By adulthood the complete ductal architechture of the gland has been established. The smallest ducts, the intralobular ducts, end in epithelial buds which are the prospective secretory alveoli.
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, the 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 is followed by abrupt involution and apoptosis during the last few days, before the onset of mestruation. The basement membrane undergoes cyclical remodelling in concert with the above cellular changes.
During pregnancy, the mammary gland epithelium experiences it's greatest and most rapid phase of proliferation. This occurs in response to hormones initially from the corpus luteum (oestrogen and progesterone), followed by placental hormones (oestrogen, progesterone and somatotropin), pituitry hormones (prolactin) and adrenocorticoids from the adrenal gland. Oestrogen exerts it's effects mainly on the ductal system, while progesterone promotes alveolar development. 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 posess 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. The adipose tissue and stroma of the gland progressively thins as the glandular components of the breast enlarge. During the third trimester, the alveoli mature. The epithelial cells become cuboidal, with an extensive basal endoplasmic reticulum, a basally situated nuclei, apical granules and cytoplasmic lipid droplets. The rate of secretion increases and the alveoli distend. Intralobular loose connective tissue surrounds the alveoli, the original dense connective tissue of the stroma has thinned to the extent that it appears as septae separating the lobules.
At parturition, there is an abrupt drop in blood oestrogen and progesterone levels. The functional gland architecture is maintained by prolactin, released from the anterior pituitry in response to a suckling stimulus from the infant. The secretory cells become fully active and produce large volumes of milk, causing the alveoli to dilate to the extent that they constitute the majority of the volume of the gland. The interlobular dense connective tissue is reduced to a fibrous capsule surrounding the lobules. The alveolar contents are expressed by contraction of the myoepithelial cells in response to oxytocin from the pituitry. For the first few days after parturition, the gland secretes colostrum, a thin milky fluid which has a low lipid content. Colostrum contains high levels of maternal antibodies, conferring passive immune protection to the infant.
At the end of the suckling period, lactation ceases. Epithelial cell numbers are reduced through apoptosis, the remaining cells become inactive and reduce in size and the alveoli and ducts regress back to a resting state. The stromal fibroblasts reconstruct the collagenous interlobular connective tissue and the gland becomes reinvested with adipose tissue. Though the post lactational breast returns to a resting state, the architecture of the gland and the composition of the supporting tissues are not identical to their structures before pregnancy.
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. As women age, the amount of elastic tissue increases, the stroma becomes more fibrous and less cellular and adopose tissue is lost. With the onset of the menopause, the levels of circulating ovarian hormones falls, the ductal elements degenerate and dense connective tissue replaces the intralobular loose connective tissue.
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Date of last revision: 26 June 1997 - 09:23:41
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