The Human Breast
Basics of Anatomy, Physiology and Development
Most breast development occurs at four primary stages—prenatal, puberty, pregnancy and lactation—with subtle changes taking place at other times of life. Before birth, the basic structures of the breast are in place. During puberty, these basic structures grow and become more complex as the breast matures. During pregnancy and lactation the breast undergoes its final stages of maturation to become fully able to make milk for the infant. These processes are guided by the body’s own hormones, but can be altered by exposure to synthetic chemicals that disrupt the way hormones are made and regulated.
This video, produced by Vassar College's Environmental Risks and Breast Cancer project, describes the critical periods of breast development and explains how exposures to toxic chemicals at susceptible stages can lead to increased risk for developing breast cancer later in life:
The breast extends from the collarbone to the lower ribs and from the sternum (breastbone) to the armpit, and consists of fat cells surrounding mammary tissues. It rests on top of the pectoralis muscle. Blood circulates through the breast, bringing nutrition and oxygen to cells of the area. The lymphatic system also travels through the breast, and includes lymph nodes on the edges of the breast, especially in the region of the armpit and the collarbone. The lymph nodes collect cellular debris and help initiate immune responses to anything threatening, such as bacteria or viruses.
The ductal system, or mammary tissue, is the critical part of the breast. Each breast has about six to eight milk ducts that travel from small bulbs called lobules within the surrounding fat of the breast and terminate at the nipple. (See Figure K.) When stimulated by the hormones secreted during pregnancy and birth, the lobules produce milk. The complexity of the ductal system depends on various factors, including age and reproductive history. (See below.)
The ductal system is fully lined with a layer of epithelial cells, the site where most breast cancers are thought to originate. During development and also during periods of relative developmental quiescence, cell-to-cell interactions between epithelial cells, as well as between epithelial cells and stromal support cells (connective cells outside the duct), are essential for maintenance of healthy tissue. Disruptions in these signaling pathways may be critical early steps in the development of cancer (Barcellos-Hoff and Medina, 2004).
Although it does not achieve full maturation and differentiation until after a first full-term pregnancy and early period of lactation, the mammary system begins to develop early in prenatal gestation. By the beginning of the mother’s second trimester of pregnancy, the fetal mammary system has gone through several weeks of differentiation and development, leading to a rudimentary system of branching buds and a primitive nipple. By the end of the second trimester, fetal breast epithelial cells produce high levels of growth factors and signals to proliferate. Neighboring stromal cells (connective cells outside the duct) are secreting protective signals that prevent developing ductal tissues from undergoing apoptosis (programmed or genetically determined cell death) and permit physical expansion of the early mammary system (Howard and Gusterson, 2000; Russo and Russo, 2004).
At birth, there is a rudimentary ductal system that empties into a well-developed nipple. The complexity of the ductal system at birth varies considerably among individuals. Regardless, at the time of full-term, normal birth, the neonatal breast is able to respond to the rise in maternal hormones to which the infant is exposed just prior to birth, and the majority of newborn infants produce and secrete small amounts of milk during the first hours or days of life (Howard and Gusterson, 2000).
Estrogen-receptor (ER) expression is first found in mammary epithelial cells at 30 weeks of gestation, and progesterone receptors (PR) are present for the first few months following birth (Keeling et al., 2000).
This period of fetal development—when the early programs for mammary tissue development are organized and the genetic and cellular signaling processes are being established for later development—is absolutely critical for later normal, healthy development of the mammary tissue. As detailed throughout this report, increasing evidence is accruing that during this early period of differentiation and development, mammary tissue is particularly sensitive to the influence of exposures to environmental toxicants, although the effects may not be observed for many years or even decades (Soto et al., 2008; Rudel et al., 2011).
With the onset of puberty, the proliferation rate of mammary system cells increases greatly, and the ducts begin to grow and divide into branches that end in small, round structures called terminal end buds (TEBs). Extensive branching leads to the formation of smaller ducts, or ductules, which end in a cluster of alveoli—cells that eventually will mature to produce and secrete milk under the conditions of lactation. These structures represent the simplest form of lobule, Lob 1 (Russo and Russo, 2004). Lob 1 epithelial cells have relatively high numbers of hormone receptors, both ER and PR, and also have a very high proliferative rate, meaning that the cells divide frequently. Although this high rate of cell division is offset considerably by balancing rates of normal cell death within the system, the presence of frequently dividing cells means that the epithelium is extraordinarily sensitive to environmental and physiological factors that may lead to later disruptions in cell signaling and possible induction of cancer.
During pregnancy and lactation, the mammary system increases in structural complexity, and lobules development progresses from the Lob 1 state to Lob 2 and Lob 3 formations. By midway through a full-term pregnancy, the milk-producing cells of the lobules, called acini, have increased in both number and size. During the final months of pregnancy, the acini fully mature into secretory epithelial cells that represent the final stage of differentiation and development of mammary tissue (Russo and Russo, 2004).
During lactation, milk is synthesized and secreted for as long as the milk release is stimulated, either through suckling or through mechanical pumping. Absent this stimulation and the release of stored milk, after a couple of days the glands begin to decrease the rate of milk synthesis, and both the ducts and the lobules regress over time to smaller, simpler forms. However, the lowered cell proliferation rates afforded by the progression of lobules from Lob 1 to Lobs 2 and 3 are retained (Russo and Russo, 2004; 2008).
During and following menopause, the mammary system in both parous women (those who have given birth) and nulliparous women (those who have never been pregnant) regresses substantially, and the profile of lobules reverts to primarily Lob 1. Although the lobular profiles look similar, the cellular differentiation resulting from early pregnancies in those women who have borne children continues to confer some protection against development of breast cancer.