Mammary Gland

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A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word mamma, \"breast\". The mammary glands are arranged in organs such as the breasts in primates (for example, humans and chimpanzees), the udder in ruminants (for example, cows, goats, sheep, and deer), and the dugs of other animals (for example, dogs and cats). Lactorrhea, the occasional production of milk by the glands, can occur in any mammal, but in most mammals, lactation, the production of enough milk for nursing, occurs only in phenotypic females who have gestated in recent months or years. It is directed by hormonal guidance from sex steroids. In a few mammalian species, male lactation can occur. With humans, male lactation can occur only under specific circumstances.

Mammals are divided into 3 groups: prototherians, metatherians, and eutherians. In the case of prototherians, both males and females have functional mammary glands, but their mammary glands are without nipples. These mammary glands are modified sebaceous glands. Concerning metatherians and eutherians, only females have functional mammary glands. Their mammary glands can be termed as breasts or udders. In the case of breasts, each mammary gland has its own nipple (e.g., human mammary glands). In the case of udders, pairs of mammary glands comprise a single mass, with more than one nipple (or teat) hanging from it. For instance, cows and buffalo each have one udder with four teats, whereas sheep and goats each have two teats protruding from the udder. These mammary glands are modified sweat glands.

A mammary gland is a specific type of apocrine gland specialized for manufacture of colostrum when giving birth. Mammary glands can be identified as apocrine because they exhibit striking \"decapitation\" secretion. Many sources assert that mammary glands are modified sweat glands.[9][10][11] Some authors dispute that and argue instead that they are sebaceous glands.[9]

Mammary glands develop during different growth cycles. They exist in both sexes during the embryonic stage, forming only a rudimentary duct tree at birth. In this stage, mammary gland development depends on systemic (and maternal) hormones,[6] but is also under the (local) regulation of paracrine communication between neighboring epithelial and mesenchymal cells by parathyroid hormone-related protein (PTHrP).[12] This locally secreted factor gives rise to a series of outside-in and inside-out positive feedback between these two types of cells, so that mammary bud epithelial cells can proliferate and sprout down into the mesenchymal layer until they reach the fat pad to begin the first round of branching.[6] At the same time, the embryonic mesenchymal cells around the epithelial bud receive secreting factors activated by PTHrP, such as BMP4. These mesenchymal cells can transform into a dense, mammary-specific mesenchyme, which later develop into connective tissue with fibrous threads, forming blood vessels and the lymph system.[13] A basement membrane, mainly containing laminin and collagen, formed afterward by differentiated myoepithelial cells, keeps the polarity of this primary duct tree. These components of the extracellular matrix are strong determinants of duct morphogenesis.[14]

Estrogen and growth hormone (GH) are essential for the ductal component of mammary gland development, and act synergistically to mediate it.[15][16][17][18][19] Neither estrogen nor GH are capable of inducing ductal development without the other.[16][17][18][19] The role of GH in ductal development has been found to be mostly mediated by its induction of the secretion of insulin-like growth factor 1 (IGF-1), which occurs both systemically (mainly originating from the liver) and locally in the mammary fat pad through activation of the growth hormone receptor (GHR).[16][17][18][19][20] However, GH itself also acts independently of IGF-1 to stimulate ductal development by upregulating estrogen receptor (ER) expression in mammary gland tissue, which is a downstream effect of mammary gland GHR activation.[19] In any case, unlike IGF-1, GH itself is not essential for mammary gland development, and IGF-1 in conjunction with estrogen can induce normal mammary gland development without the presence of GH.[19] In addition to IGF-1, other paracrine growth factors such as epidermal growth factor (EGF), transforming growth factor beta (TGF-β),[21] amphiregulin,[22] fibroblast growth factor (FGF), and hepatocyte growth factor (HGF)[23] are involved in breast development as mediators downstream to sex hormones and GH/IGF-1.[24][25][26]

During embryonic development, IGF-1 levels are low, and gradually increase from birth to puberty.[27] At puberty, the levels of GH and IGF-1 reach their highest levels in life and estrogen begins to be secreted in high amounts in females, which is when ductal development mostly takes place.[27] Under the influence of estrogen, stromal and fat tissue surrounding the ductal system in the mammary glands also grows.[28] After puberty, GH and IGF-1 levels progressively decrease, which limits further development until pregnancy, if it occurs.[27] During pregnancy, progesterone and prolactin are essential for mediating lobuloalveolar development in estrogen-primed mammary gland tissue, which occurs in preparation of lactation and nursing.[15][29]

Androgens such as testosterone inhibit estrogen-mediated mammary gland development (e.g., by reducing local ER expression) through activation of androgen receptors expressed in mammary gland tissue,[29][30] and in conjunction with relatively low estrogen levels, are the cause of the lack of developed mammary glands in males.[31]

Mammary gland development is characterized by the unique process by which the epithelium invades the stroma. The development of the mammary gland occurs mainly after birth. During puberty, tubule formation is coupled with branching morphogenesis which establishes the basic arboreal network of ducts emanating from the nipple.[32]

Developmentally, mammary gland epithelium is constantly produced and maintained by rare epithelial cells, dubbed as mammary progenitors which are ultimately thought to be derived from tissue-resident stem cells.[33]

Embryonic mammary gland development can be divided into a series of specific stages. Initially, the formation of the milk lines that run between the fore and hind limbs bilaterally on each side of the midline occurs around embryonic day 10.5 (E10.5). The second stage occurs at E11.5 when placode formation begins along the mammary milk line. This will eventually give rise to the nipple. Lastly, the third stage occurs at E12.5 and involves the invagination of cells within the placode into the mesenchyme, leading to a mammary anlage (biology).[34]

By the pubertal stage, the mammary ducts have invaded to the end of the mammary fat pad. At this point, the terminal end buds become less proliferative and decrease in size. Side branches form from the primary ducts and begin to fill the mammary fat pad. Ductal development decreases with the arrival of sexual maturity and undergoes estrous cycles (proestrus, estrus, metestrus, and diestrus). As a result of estrous cycling, the mammary gland undergoes dynamic changes where cells proliferate and then regress in an ordered fashion.[36]

During pregnancy, the ductal systems undergo rapid proliferation and form alveolar structures within the branches to be used for milk production. After delivery, lactation occurs within the mammary gland; lactation involves the secretion of milk by the luminal cells in the alveoli. Contraction of the myoepithelial cells surrounding the alveoli will cause the milk to be ejected through the ducts and into the nipple for the nursing infant. Upon weaning of the infant, lactation stops and the mammary gland turns in on itself, a process called involution. This process involves the controlled collapse of mammary epithelial cells where cells begin apoptosis in a controlled manner, reverting the mammary gland back to a pubertal state.

Lactiferous duct development occurs in females in response to circulating hormones. First development is frequently seen during pre- and postnatal stages, and later during puberty. Estrogen promotes branching differentiation,[37] whereas in males testosterone inhibits it. A mature duct tree reaching the limit of the fat pad of the mammary gland comes into being by bifurcation of duct terminal end buds (TEB), secondary branches sprouting from primary ducts[7][38] and proper duct lumen formation. These processes are tightly modulated by components of mammary epithelial ECM interacting with systemic hormones and local secreting factors. However, for each mechanism the epithelial cells' \"niche\" can be delicately unique with different membrane receptor profiles and basement membrane thickness from specific branching area to area, so as to regulate cell growth or differentiation sub-locally.[39] Important players include beta-1 integrin, epidermal growth factor receptor (EGFR), laminin-1/5, collagen-IV, matrix metalloproteinase (MMPs), heparan sulfate proteoglycans, and others. Elevated circulating level of growth hormone and estrogen get to multipotent cap cells on TEB tips through a thin, leaky layer of basement membrane. These hormones promote specific gene expression. Hence cap cells can differentiate into myoepithelial and luminal (duct) epithelial cells, and the increased amount of activated MMPs can degrade surrounding ECM helping duct buds to reach further in the fat pads.[40][41] On the other hand, basement membrane along the mature mammary ducts is thicker, with strong adhesion to epithelial cells via binding to integrin and non-integrin receptors. When side branches develop, it is a much more \"pushing-forward\" working process including extending through myoepithelial cells, degrading basement membrane and then invading into a periductal layer of fibrous stromal tissue.[7] Degraded basement membrane fragments (laminin-5) roles to lead the way of mammary epithelial cells migration.[42] Whereas, laminin-1 interacts with non-integrin receptor dystroglycan negatively regulates this side branching process in case of cancer.[43] These complex \"Yin-yang\" balancing crosstalks between mammary ECM and epithelial cells \"instruct\" healthy mammary gland development until adult. 59ce067264

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