||It has been suggested that Mammary gland development be merged into this article. (Discuss) Proposed since January 2015.|
|Mammary gland in a human female|
Dissection of a lactating breast
(blood vessels and connective tissue)
|Internal thoracic artery
Lateral thoracic artery
|Internal thoracic vein
(lateral and medial branches)
|Pectoral axillary lymph nodes|
A mammary gland is an organ in female mammals that produces milk to feed young offspring. Mammals get their name from the word "mammary." In humans, the mammary glands are situated in the breasts. In ruminants such as cows, goats, and deer, the mammary glands are contained in the udders. The mammary glands of mammals other than primates, such as dogs and cats, are sometimes called dugs.
The basic components of a mature mammary gland are the alveoli (hollow cavities, a few millimeters large) lined with milk-secreting cuboidal cells and surrounded by myoepithelial cells. These alveoli join to form groups known as lobules. Each lobule has a lactiferous duct that drains into openings in the nipple. The myoepithelial cells contract under the stimulation of oxytocin, excreting the milk secreted by alveolar units into the lobule lumen toward the nipple. As the infant begins to suck, the oxytocin-mediated "let down reflex" ensues and the mother's milk is secreted — not sucked from the gland — into the baby's mouth.
All the milk-secreting tissue leading to a single lactiferous duct is 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 presence of more than two nipples is known as polythelia and the presence of more than two complex mammary glands as polymastia.
Maintaining the correct polarized morphology of the lactiferous duct tree requires another essential component – mammary epithelial cells extracellular matrix (ECM) which, together with adipocytes, fibroblast, inflammatory cells, and others, constitute mammary stroma. Mammary epithelial ECM mainly contains myoepithelial basement 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.
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. Some authors dispute that and argue instead that they are sebaceous glands.
Mammary glands develop during different growth cycles. They exist in both sexes during embryonic stage, forming only a rudimentary duct tree at birth. In this stage, mammary gland development depends on systemic (and maternal) hormones, but is also under the (local) regulation of paracrine communication between neighboring epithelial and mesenchymal cells by parathyroid hormone-related protein (PTHrP). 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. 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. A basement membrane, mainly containing laminin and collagen, formed afterward by differentiated myoepithelial cells, keeps the polarity of this primary duct tree.
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, 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 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. 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. 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. Degraded basement membrane fragments (laminin-5) roles to lead the way of mammary epithelial cells migration. Whereas, laminin-1 interacts with non-integrin receptor dystroglycan negatively regulates this side branching process in case of cancer. These complex "Yin-yang" balancing crosstalks between mammary ECM and epithelial cells "instruct" healthy mammary gland development until adult.
Secretory alveoli develop mainly in pregnancy, when rising levels of prolactin, estrogen, and progesterone cause further branching, together with an increase in adipose tissue and a richer blood flow. In gestation, 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. 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 circulating progesterone and the presence of another important hormone prolactin, which mediates further alveologenesis, milk protein production, and regulates osmotic balance and tight junction function. Laminin and collagen in myoepithelial basement membrane interacting with beta-1 integrin on epithelial surface again, is essential in this process. Their binding ensures correct placement of prolactin receptors on the basal lateral side of alveoli cells and directional secretion of milk into lactiferous ducts. 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. In some species there is complete or partial involution 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. In some other species (such as cows), all alveoli and secretory duct structures collapse by programmed cell death (apoptosis) and autophagy for lack of growth promoting factors either from the ECM or circulating hormones. At the same time, apoptosis of blood capillary endothelial cells speeds up the regression of lactation ductal beds. Shrinkage of the mammary duct tree and ECM remodeling by various proteinase is under the control of somatostatin and other growth inhibiting hormones and local factors. 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, or from a mechanical change in the tension of mammary stroma. Under either of the two circumstances, mammary epithelial cells would grow out of control and eventually result in cancer. Almost all instances of breast cancer originate in the lobules or ducts of the mammary glands.
The constantly protruding breasts of the adult human female, unusually large relative to body size, are a unique evolutionary development whose purpose is not yet fully known (see breast); other mammals tend to have less conspicuous mammary glands that protrude only while actually filling with milk. The number and positioning of complex and simple mammary glands varies widely in different mammals. The nipples and glands can occur anywhere along the two milk lines, two nearly parallel lines along the ventral aspect of the body. 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 nipples varies from 2 (in most primates) to 18 (in pigs). The Virginia Opossum has 13, one of the few mammals with an odd number. The following table lists the number and position of glands normally found in a range of mammals:
|Goat, sheep, horse
|Dog||4||2||2 or 4||8 or 10|
Male mammals typically have rudimentary mammary glands and nipples, with a few exceptions: male mice do not have nipples, and male horses lack nipples and mammary glands. The male Dayak fruit bat has lactating mammary glands. Male lactation occurs infrequently in some species, including humans.
Mammary glands are true protein factories, and several labs have constructed transgenic animals, mainly goats and cows, to produce proteins for pharmaceutical use. Complex glycoproteins such as monoclonal antibodies or antithrombin cannot be produced by genetically engineered bacteria, and the production in live mammals is much cheaper than the use of mammalian cell cultures.
The evolution of the mammary gland is difficult to explain; this is because mammary glands are typically required by mammals to feed their young. There are many theories on how mammary glands evolved, for example, it is believed that the mammary gland is a transformed sweat gland, more closely related to apocrine sweat glands. Since 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 and eutherians. One theory proposes that mammary glands evolved from glands that were used to keep the eggs of early mammals moist and free from infection (monotremes still lay eggs). Other theories suggest that early secretions were used directly by hatched young, or that the secretions were used by young to help them orient to their mothers.
Lactation is thought to have developed long before the evolution of the mammary gland and mammals; see evolution of lactation.
- This article uses anatomical terminology; for an overview, see anatomical terminology.
- Mammary tumor
- Witch's milk
- Milk line
- List of glands of the human body#Skin
- Gray, Henry (1918). Anatomy of the Human Body.
- Macéa, José Rafael; Fregnani, José Humberto Tavares Guerreiro (1 December 2006). "Anatomy of the Thoracic Wall, Axilla and Breast". International Journal of Morphology 24 (4). doi:10.4067/S0717-95022006000500030.
- Lawrence, Ruth A.; Lawrence, Robert M. Breastfeeding: A Guide for the Medical Profession (7th ed.). Maryland Heights, Maryland: Mosby/Elsevier. p. 54. ISBN 9781437735901.
- Watson, C. J.; Khaled, W. T. (2008). "Mammary development in the embryo and adult: A journey of morphogenesis and commitment". Development 135 (6): 995–1003. doi:10.1242/dev.005439. PMID 18296651.
- Wiseman, B. S.; Werb, Z. (2002). "Stromal Effects on Mammary Gland Development and Breast Cancer". Science 296 (5570): 1046–1049. doi:10.1126/science.1067431. PMC 2788989. PMID 12004111.
- Pavlovich, A. L.; Manivannan, S.; Nelson, C. M. (2010). "Adipose Stroma Induces Branching Morphogenesis of Engineered Epithelial Tubules". Tissue Engineering Part A 16 (12): 3719–3726. doi:10.1089/ten.TEA.2009.0836. PMC 2991209. PMID 20649458.
- Ackerman (2005) ch.1 Apocrine Units
- Moore (2010) ch.1 Thorax, p. 99
- Krstic, Radivoj V. (18 March 2004). Human Microscopic Anatomy: An Atlas for Students of Medicine and Biology. Springer. p. 466. ISBN 9783540536666.
- Wysolmerski, J. J.; Philbrick, W. M.; Dunbar, M. E.; Lanske, B.; Kronenberg, H.; Broadus, A. E. (1998). "Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development". Development (Cambridge, England) 125 (7): 1285–1294. PMID 9477327.
- Hens, J. R.; Wysolmerski, J. J. (2005). "Key stages of mammary gland development: Molecular mechanisms involved in the formation of the embryonic mammary gland". Breast Cancer Research 7 (5): 220–224. doi:10.1186/bcr1306. PMC 1242158. PMID 16168142.
- Sternlicht, M. D. (2006). "Key stages in mammary gland development: The cues that regulate ductal branching morphogenesis". Breast Cancer Research 8 (1): 201–203. doi:10.1186/bcr1368. PMC 1413974. PMID 16524451.
- Sternlicht, M. D.; Kouros-Mehr, H.; Lu, P.; Werb, Z. (2006). "Hormonal and local control of mammary branching morphogenesis". Differentiation 74 (7): 365–381. doi:10.1111/j.1432-0436.2006.00105.x. PMC 2580831. PMID 16916375.
- Fata, J. E.; Werb, Z.; Bissell, M. J. (2003). "Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes". Breast Cancer Research 6 (1): 1–11. doi:10.1186/bcr634. PMC 314442. PMID 14680479.
- Wiseman, B. S.; Sternlicht, M. D.; Lund, L. R.; Alexander, C. M.; Mott, J.; Bissell, M. J.; Soloway, P.; Itohara, S.; Werb, Z. (2003). "Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis". The Journal of Cell Biology 162 (6): 1123–1133. doi:10.1083/jcb.200302090. PMC 2172848. PMID 12975354.
- Koshikawa, N.; Giannelli, G.; Cirulli, V.; Miyazaki, K.; Quaranta, V. (2000). "Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5". The Journal of cell biology 148 (3): 615–624. doi:10.1083/jcb.148.3.615. PMC 2174802. PMID 10662785.
- Dogic, D.; Rousselle, P.; Aumailley, M. (1998). "Cell adhesion to laminin 1 or 5 induces isoform-specific clustering of integrins and other focal adhesion components" (PDF). Journal of cell science. 111 (Pt 6): 793–802. PMID 9472007.
- Muschler, J.; Levy, D.; Boudreau, R.; Henry, M.; Campbell, K.; Bissell, M. J. (2002). "A role for dystroglycan in epithelial polarization: Loss of function in breast tumor cells". Cancer research 62 (23): 7102–7109. PMID 12460932.
- Kurzer MS (March 2002). "Hormonal effects of soy in premenopausal women and men". The Journal of Nutrition 132 (3): 570S–573S. PMID 11880595. Also cited by Petrakis NL, Barnes S, King EB, Lowenstein J, Wiencke J, Lee MM, Miike R, Kirk M, Coward L (October 1996). "Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women". Cancer Epidemiology, Biomarkers & Prevention: a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology (review) 5 (10): 785–94. PMID 8896889.
- Robinson, G. W.; Hennighausen, L.; Johnson, P. F. (2000). "Side-branching in the mammary gland: The progesterone-Wnt connection". Genes & development 14 (8): 889–894. PMID 10783160.
- Brisken, C.; Heineman, A.; Chavarria, T.; Elenbaas, B.; Tan, J.; Dey, S. K.; McMahon, J. A.; McMahon, A. P.; Weinberg, R. A. (2000). "Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling". Genes & development 14 (6): 650–654. PMC 316462. PMID 10733525.
- Streuli, C. H.; Bailey, N.; Bissell, M. J. (1991). "Control of mammary epithelial differentiation: Basement membrane induces tissue-specific gene expression in the absence of cell-cell interaction and morphological polarity". The Journal of cell biology 115 (5): 1383–1395. doi:10.1083/jcb.115.5.1383. PMC 2289247. PMID 1955479.
- Streuli, C. H.; Schmidhauser, C.; Bailey, N.; Yurchenco, P.; Skubitz, A. P.; Roskelley, C.; Bissell, M. J. (1995). "Laminin mediates tissue-specific gene expression in mammary epithelia". The Journal of cell biology 129 (3): 591–603. doi:10.1083/jcb.129.3.591. PMC 2120432. PMID 7730398.
- Nicholas L. Petrakis; Lynn Mason; Rose Lee; Barbara Sugimoto; Stella Pawson; Frank Catchpool (1975). "Association of Race, Age, Menopausal Status, and Cerumen Type With Breast Fluid Secretion in Nonlactating Women, as Determined by Nipple Aspiration". Journal of the National Cancer Institute (JNCI) 54 (4): 829–834. doi:10.1093/jnci/54.4.829.
- Zarzynska, J.; Motyl, T. (2008). "Apoptosis and autophagy in involuting bovine mammary gland". Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 59 Suppl 9: 275–288. PMID 19261986.
- Fadok, V. A. (1999). "Clearance: The last and often forgotten stage of apoptosis". Journal of mammary gland biology and neoplasia 4 (2): 203–211. doi:10.1023/A:1011384009787. PMID 10426399.
- Motyl, T.; Gajkowska, B.; Zarzyńska, J.; Gajewska, M.; Lamparska-Przybysz, M. (2006). "Apoptosis and autophagy in mammary gland remodeling and breast cancer chemotherapy". Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 57 Suppl 7: 17–32. PMID 17228094.
- Gudjonsson, T.; Rønnov-Jessen, L.; Villadsen, R.; Rank, F.; Bissell, M. J.; Petersen, O. W. (2002). "Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition". Journal of cell science 115 (Pt 1): 39–50. PMC 2933194. PMID 11801722.
- Provenzano, P. P.; Inman, D. R.; Eliceiri, K. W.; Knittel, J. G.; Yan, L.; Rueden, C. T.; White, J. G.; Keely, P. J. (2008). "Collagen density promotes mammary tumor initiation and progression". BMC Medicine 6: 11. doi:10.1186/1741-7015-6-11. PMC 2386807. PMID 18442412.
- "With the Wild Things – Transcripts". Digitalcollections.fiu.edu. Retrieved 2013-04-05.
- Stockard, Mary (2005) Raising Orphaned Baby Opossums. Alabama Wildlife Center.
- Cunningham, Merle; LaTour, Mickey A. and Acker, Duane (2005). Animal Science and Industry. Pearson Prentice Hall. ISBN 978-0-13-046256-5.
- Dog breeds vary in the number of mammary glands: larger breeds tend to have 5 pairs, smaller breeds have 4 pairs.
- Julie Ann Mayer; John Foley; Damon De La Cruz; Cheng-Ming Chuong; Randall Widelitz (November 2008). "Conversion of the Nipple to Hair-Bearing Epithelia by Lowering Bone Morphogenetic Protein Pathway Activity at the Dermal-Epidermal Interface".
- Francis, C. M.; Anthony, E. L. P.; Brunton, J. A.; Kunz, T. H. (1994). "Lactation in male fruit bats" (PDF). Nature 367 (6465): 691. doi:10.1038/367691a0.
- "BBC News – The goats with spider genes and silk in their milk". bbc.co.uk. 17 January 2012. Retrieved 26 April 2012.
- Oftedal, O. T. (2002). "The origin of lactation as a water source for parchment-shelled eggs". Journal of mammary gland biology and neoplasia 7 (3): 253–266. doi:10.1023/A:1022848632125. PMID 12751890.
- Lactating on Eggs. Smithsonian National Zoo, July 14, 2003.
- Oftedal, OT (2002). "The mammary gland and its origin during synapsid evolution". Journal of Mammary Gland Biology and Neoplasia 7 (3): 225–52. doi:10.1023/A:1022896515287. PMID 12751889.
- Breast beginnings. scienceblogs.com
- Vorbach, C.; Capecchi, M. R.; Penninger, J. M. (2006). "Evolution of the mammary gland from the innate immune system?". BioEssays 28 (6): 606–616. doi:10.1002/bies.20423. PMID 16700061.
- Lefèvre, C. M.; Sharp, J. A.; Nicholas, K. R. (2010). "Evolution of Lactation: Ancient Origin and Extreme Adaptations of the Lactation System". Annual Review of Genomics and Human Genetics 11: 219–238. doi:10.1146/annurev-genom-082509-141806. PMID 20565255.
- Graves, B. M.; Duvall, D. (1983). "A Role for Aggregation Pheromones in the Evolution of Mammallike Reptile Lactation". The American Naturalist 122 (6): 835. doi:10.1086/284177.
- Ackerman, A. Bernard; Almut Böer; Bruce Bennin; Geoffrey J. Gottlieb (2005). Histologic Diagnosis of Inflammatory Skin Diseases An Algorithmic Method Based on Pattern Analysis. ISBN 978-1-893357-25-9.
- Moore, Keith L. et al. (2010) Clinically Oriented Anatomy 6th Ed
- Comparative Mammary Gland Anatomy by W. L. Hurley
- On the anatomy of the breast by Sir Astley Paston Cooper (1840). Numerous drawings, in the public domain.