Amammary gland is anexocrine gland that producesmilk inhumans and othermammals. Mammals get their name from the Latin wordmamma, "breast". The mammary glands are arranged inorgans such as thebreasts in primates (for example, humans and chimpanzees), theudder inruminants (for example, cows, goats, sheep, and deer), and thedugs of other animals (for example, dogs and cats) to feed youngoffspring.Lactorrhea, the occasional production of milk by the glands, can occur in any mammal, but in most mammals,lactation, the production of enough milk fornursing, occurs only inphenotypicfemales who havegestated in recent months or years. It is directed by hormonal guidance fromsex 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:monotremes,metatherians, andeutherians. In the case of monotremes, their mammary glands are modifiedsebaceous glands and without nipples. Concerning most metatherians and eutherians, only females have functional mammary glands, with the exception of some bat species. Their mammary glands can be termed as breasts orudders. 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 (orteat) hanging from it. For instance, cows and buffalo udders have two pairs of mammary glands and four teats, whereas sheep and goat udders have one pair of mammary glands with two teats protruding from the udder. Each mammary gland produces milk for a single teat and is evolutionarily derived from modified sweat glands.
The basic components of a mature mammary gland are thealveoli (hollow cavities, a few millimeters large), which are lined with milk-secretingcuboidal cells and surrounded bymyoepithelial cells. These alveoli join to form groups known aslobules. Each lobule has alactiferous duct that drains into openings in thenipple. The myoepithelial cells contract under the stimulation ofoxytocin, excreting the milk secreted by alveolar units into the lobule lumen toward the nipple. As theinfant begins to suck, the oxytocin-mediated "let down reflex" ensues, and the mother's milk is secreted—not sucked—from the gland into the infant's mouth.[4]
All the milk-secreting tissue leading to a single lactiferous duct is collectively called a "simple mammary gland"; in a "complex mammary gland", all the simple mammary glands serve one nipple. Humans normally have two complex mammary glands, one in each breast, and each complex mammary gland consists of 10–20 simple glands. The opening of each simple gland on the surface of the nipple is called a "pore."[5] The presence of more than two nipples is known aspolythelia and the presence of more than two complex mammary glands aspolymastia.
Maintaining the correct polarized morphology of the lactiferous duct tree requires another essential component – mammary epithelial cellsextracellular matrix (ECM) which, together withadipocytes,fibroblast, inflammatory cells, and others, constitute mammary stroma.[6] Mammary epithelial ECM mainly contains myoepithelialbasement membrane and the connective tissue. They not only help to support mammary basic structure, but also serve as a communicating bridge between mammary epithelia and their local and global environment throughout this organ's development.[7][8]
Normal histology of the breastLight micrograph of a human proliferating mammary gland during estrous cycle. Sprouting gland tissue can be seen in the upper left field (haematoxylin eosin staining).
A mammary gland is a specific type ofapocrine gland specialized for manufacture ofcolostrum (first milk) when giving birth. Mammary glands can be identified as apocrine because they exhibit striking "decapitation" secretion. Many sources assert that mammary glands are modifiedsweat glands.[9][10][11]
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 ofparacrine 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 byPTHrP, such asBMP4. 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 containinglaminin andcollagen, 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 andgrowth hormone (GH) are essential for theductal 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 ofinsulin-like growth factor 1 (IGF-1), which occurs both systemically (mainly originating from theliver) and locally in the mammary fat pad through activation of thegrowth hormone receptor (GHR).[16][17][18][19][20] However, GH itself also acts independently of IGF-1 to stimulate ductal development by upregulatingestrogen 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, otherparacrinegrowth factors such asepidermal growth factor (EGF),transforming growth factor beta (TGF-β),[21]amphiregulin,[22]fibroblast growth factor (FGF), andhepatocyte 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 andfat 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 untilpregnancy, if it occurs.[27] During pregnancy,progesterone andprolactin are essential for mediatinglobuloalveolar development in estrogen-primed mammary gland tissue, which occurs in preparation oflactation andnursing.[15][29]
Androgens such astestosterone inhibit estrogen-mediated mammary gland development (e.g., by reducing local ER expression) through activation ofandrogen 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 theepithelium invades thestroma. The development of the mammary gland occurs mainly afterbirth. Duringpuberty, tubule formation is coupled withbranching morphogenesis which establishes the basic arboreal network of ducts emanating from thenipple.[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 whenplacode 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 theinvagination of cells within theplacode into themesenchyme, leading to a mammaryanlage (biology).[34]
The primitive (stem) cells are detected in embryo and their numbers increase steadily during development[35]
Postnatally, the mammary ducts elongate into the mammary fat pad. Then, starting around four weeks of age, mammary ductal growth increases significantly with the ducts invading towards thelymph node. Terminal end buds, the highly proliferative structures found at the tips of the invading ducts, expand and increase greatly during this stage. This developmental period is characterized by the emergence of the terminal end buds and lasts until an age of about 7–8 weeks.
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 ofsexual maturity and undergoesestrous 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]
Duringpregnancy, the ductal systems undergo rapid proliferation and formalveolar 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 theluminal cells in the alveoli. Contraction of themyoepithelial cells surrounding the alveoli will cause the milk to be ejected through the ducts and into the nipple for the nursing infant. Uponweaning of the infant, lactation stops and the mammary gland turns in on itself, a process calledinvolution. This process involves the controlled collapse of mammary epithelial cells where cells beginapoptosis in a controlled manner, reverting the mammary gland back to a pubertal state.
Duringpostmenopause, due to much lower levels of estrogen, and due to lower levels of GH and IGF-1, which decrease with age, mammary gland tissue atrophies and the mammary glands become smaller.
Lactiferous duct development occurs in females in response to circulatinghormones. First development is frequently seen during pre- and postnatal stages, and later duringpuberty.Estrogen promotes branching differentiation,[37] whereas in malestestosterone inhibits it. A mature duct tree reaching the limit of the fat pad of the mammary gland comes into being by bifurcation of ductterminal 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 includebeta-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 tomultipotent cap cells on TEB tips through a thin, leaky layer of basement membrane. These hormones promote specific gene expression. Hence cap cells can differentiate intomyoepithelial 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 tointegrin 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 receptordystroglycan negatively regulates this side branching process in case ofcancer.[43] These complex "Yin-yang" balancing crosstalks between mammary ECM and epithelial cells "instruct" healthy mammary gland development until adult.
There is preliminary evidence thatsoybean intake mildly stimulates the breast glands in pre- and postmenopausal women.[44]
Secretory alveoli develop mainly in pregnancy, when rising levels ofprolactin, estrogen, and progesterone cause further branching, together with an increase inadipose tissue and a richerblood flow. Ingestation, serum progesterone remains at a stably high concentration so signaling through its receptor is continuously activated. As one of the transcribed genes,Wnts secreted from mammary epithelial cells act paracrinely to induce more neighboring cells' branching.[45][46] When the lactiferous duct tree is almost ready, "leaves" alveoli are differentiated from luminal epithelial cells and added at the end of each branch. In late pregnancy and for the first few days after giving birth,colostrum is secreted. Milk secretion (lactation) begins a few days later due to reduction in circulatingprogesterone and the presence of another important hormone prolactin, which mediates further alveologenesis, milk protein production, and regulates osmotic balance andtight junction function. Laminin and collagen in myoepithelial basement membrane interacting with beta-1integrin on epithelial surface again, is essential in this process.[47][48] Their binding ensures correct placement of prolactin receptors on the basal lateral side of alveoli cells and directional secretion of milk into lactiferous ducts.[47][48] Suckling of the baby causes release of the hormone oxytocin, which stimulates contraction of the myoepithelial cells. In this combined control from ECM and systemic hormones, milk secretion can be reciprocally amplified so as to provide enough nutrition for the baby.
During weaning, decreased prolactin, missing mechanical stimulation (baby suckling), and changes in osmotic balance caused by milk stasis and leaking of tight junctions cause cessation of milk production. It is the (passive) process of a child or animal ceasing to be dependent on the mother for nourishment. In some species there is complete or partialinvolution of alveolar structures after weaning, in humans there is only partial involution and the level of involution in humans appears to be highly individual. The glands in the breast do secrete fluid also in nonlactating women.[49] In some other species (such as cows), all alveoli and secretory duct structures collapse by programmed cell death (apoptosis) andautophagy for lack of growth promoting factors either from the ECM or circulating hormones.[50][51] At the same time, apoptosis of blood capillaryendothelial cells speeds up the regression of lactation ductal beds. Shrinkage of the mammary duct tree and ECM remodeling by variousproteinase is under the control ofsomatostatin and other growth inhibiting hormones and local factors.[52] This major structural change leads loose fat tissue to fill the empty space afterward. But a functional lactiferous duct tree can be formed again when a female is pregnant again.
Tumorigenesis in mammary glands can be induced biochemically by abnormal expression level of circulating hormones or local ECM components,[53] or from a mechanical change in the tension of mammary stroma.[54] Under either of the two circumstances, mammary epithelial cells would grow out of control and eventually result in cancer. Almost all instances ofbreast cancer originate in the lobules or ducts of the mammary glands.
The breasts of female humans vary from most other mammals that tend to have less conspicuous mammary glands. The number and positioning of mammary glands varies widely in different mammals. The protruding teats and accompanying glands can be located anywhere along the twomilk lines. In general most mammals develop mammary glands in pairs along these lines, with a number approximating the number of young typically birthed at a time. The number of teats varies from 2 (in most primates) to 18 (in pigs). TheVirginia opossum has 13, one of the few mammals with an odd number.[55][56] The following table lists the number and position of teats and glands found in a range of mammals:
Male mammals typically have rudimentary mammary glands and nipples, with a few exceptions: male mice do not have nipples,[60] malemarsupials do not have mammary glands,[61] and male horses lack nipples.[62] The maledayak fruit bat has lactating mammary glands.[63]Male lactation occurs infrequently in some species.[64]
There are many theories on how mammary glands evolved. For example, it is thought that the mammary gland is a transformed sweat gland, more closely related toapocrine sweat glands.[67] Because mammary glands do not fossilize well, supporting such theories with fossil evidence is difficult. Many of the current theories are based on comparisons between lines of living mammals—monotremes,marsupials, andeutherians. One theory proposes that mammary glands evolved from glands that were used to keep the eggs of early mammals moist[68][69] and free from infection[70][71] (monotremes still lay eggs). Other theories suggest that early secretions were used directly by hatched young,[72] or that the secretions were used by young to help them orient to their mothers.[73]
Lactation is thought to have developed long before the evolution of the mammary gland and mammals; seeevolution of lactation.
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