NEW INSIGHTS OF MAMMARY GLAND DURING DIFFERENT STAGES OF DEVELOPMENT
Â Mammary gland is a unique organ with its function of milk synthesis, secretion, and involution to prepare the gland for subsequent lactation. The mammary epithelial cells proliferate, differentiate, undergo apoptosis, and tissue remodeling following a cyclic pathway in lactation â€“ involution â€“ lactation cycle, thus fine tuning the molecular events through hormones, and regulatory molecules. Several studies are performed on the mammary gland development, lactogenesis, and involution process in molecular details. The developmental stages of mammary gland are embryonic, pre-pubertal, pubertal, pregnancy, lactation, and involution. Major developmental processes occur after puberty with hormones and growth factors playing crucial role. The two major pathways such as Janus kinases-signal transducer and activator of transcription pathway and PI3K-Akt pathway play a major role in maintaining the lactation. The involution process is a well-orchestrated event involving several signaling molecules and making the gland ready for subsequent lactation. The review focuses on findings with molecular details of different stages of the mammary gland development and signaling pathways involved in lactationâ€“involution cycle. Deep insight into the developmental stages of mammary gland will pave the way to understand mammary gland biology, apoptosis, oncogenesis, and it will help the researchers to use mammary gland as a model for research on various aspects. Â
buffalo (Bubalus bubalis): Lactating vis-a-vis heifer. J Proteomics 2015;119:100-11.
2. DesriviÃ¨res S, Kuhn K, MÃ¼ller J, GlÃ¤ser M, Laria NC, Korder J, et al. Comparison of the nuclear proteomes of mammary epithelial cells at different stages of functional differentiation. Proteomics 2007;7(12):2019-37.
3. Hennighausen L, Robinson GW. Signaling pathways in mammary gland development. Dev Cell 2001;1(4):467-75.
4. Janjanam J, Jamwal M, Singh S, Kumar S, Panigrahi AK, Hariprasad G, et al. Proteome analysis of functionally differentiated bovine (Bos indicus) mammary epithelial cells isolated from milk. Proteomics 2013;13(21):3189-204.
5. Brisken C, Rajaram RD. Alveolar and lactogenic differentiation. J Mammary Gland Biol Neoplasia 2006;11(3-4):239-48.
6. Lund LR, RÃ¸mer J, Thomasset N, Solberg H, Pyke C, Bissell MJ, et al. Two distinct phases of apoptosis in mammary gland involution: Proteinase-independent and-dependent pathways. Development 1996;122(1):181-93.
7. Watson CJ, Kreuzaler PA. Remodeling mechanisms of the mammary gland during involution. Int J Dev Biol 2011;55(7-9):757-62.
8. Sonstegard TS, Capuco AV, White J, Van Tassell CP, Connor EE, Cho J, et al. Analysis of bovine mammary gland EST and functional annotation of the Bos taurus gene index. Mamm Genome 2002;13(7):373-9.
9. Suchyta SP, Sipkovsky S, Halgren RG, Kruska R, Elftman M, Weber-Nielsen M, et al. Bovine mammary gene expression profiling using a cDNA microarray enhanced for mammary-specific transcripts. Physiol Genomics 2003;16(1):8-18.
10. Clarkson RW, Wayland MT, Lee J, Freeman T, Watson CJ. Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression. Breast Cancer Res 2004;6(2):R92-109.
11. Stein T, Morris JS, Davies CR, Weber-Hall SJ, Duffy MA, Heath VJ, et al. Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3. Breast Cancer Res 2004;6(2):R75-91.
12. Finucane KA, McFadden TB, Bond JP, Kennelly JJ. Zhao FQ. Onset of lactation in the bovine mammary gland: Gene expression profiling indicates a strong inhibition of gene expression in cell proliferation. Funct Integr Genomics 2008;8(3):251-64.
13. Hartmann P, Cregan M. Lactogenesis and the effects of insulin-dependent diabetes mellitus and prematurity. J Nutr 2001;131(11):3016S-20.
14. Praveesh BV, Angayarkanni J, Palaniswamy M. Antihypertensive and anticancer effect of cow milk fermented by Lactobacillus plantarum and Lactobacillus casei. Int J Pharm Pharm Sci 2011;3 Suppl 5:452-6.
15. Oftedal OT. The mammary gland and its origin during synapsid evolution. J Mammary Gland Biol Neoplasia 2002;7(3):225-52.
16. Husveth F. Physiological and Reproductional Aspects of Animal Production. Debrecen, Hungary: Debreceni Egyetem; 2011.
17. Watson CJ, Khaled WT. Mammary development in the embryo and adult: A journey of morphogenesis and commitment. Development 2008;135(6):995-1003.
18. Andrechek ER, Mori S, Rempel RE, Chang JT, Nevins JR. Patterns of cell signaling pathway activation that characterize mammary development. Development 2008;135(14):2403-13.
19. Larson BL, editor. Lactation: A Comprehensive Treatise. Vol. 1-3. New York: Academic; 1978.
20. Veltmaat JM, Van Veelen W, Thiery JP, Bellusci S. Identification of the mammary line in mouse by Wnt10b expression. Dev Dyn 2004;229(2):349-56.
21. Hens JR, Dann P, Zhang JP, Harris S, Robinson GW, Wysolmerski J. BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction. Development 2007;134(6):1221-30.
22. Humphreys RC, Krajewska M, Krnacik S, Jaeger R, Weiher H, Krajewski S, et al. Apoptosis in the terminal end bud of the murine mammary gland: A mechanism of ductal morphogenesis. Development 1996;122(12):4013-22.
23. Asselin-Labat ML, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC, et al. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol 2007;9(2):201-9.
24. Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 2006;127(5):1041-55.
25. Peuhu E, Kaukonen R, Lerche M, Saari M, GuzmÃ¡n C, Rantakari P, et al. SHARPIN regulates collagen architecture and ductal outgrowth in the developing mouse mammary gland. EMBO J 2017;36(2):165-82.
26. Feng Y, Manka D, Wagner KU, Khan SA. Estrogen receptor-alpha expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice. Proc Natl Acad Sci U S A 2007;104(37):14718-23.
27. Ensslin MA, Shur BD. The EGF repeat and discoidin domain protein, SED1/MFG-E8, is required for mammary gland branching morphogenesis. Proc Natl Acad Sci U S A 2007;104(8):2715-20.
28. Mehta RG, Hawthorne M, Mehta RR, Torres KE, Peng X, McCormick DL, et al. Differential roles of ERÎ± and ERÎ² in normal and neoplastic development in the mouse mammary gland. PLoS One 2014;9(11):e113175.
29. Lakshmi R, Vijayalakshmi S, Raju A, Joy TM. Assessment of various risk factors of breast cancer. Int J Pharm Pharm Sci 2013; 5 Suppl 4:675-8.
30. Wright LC, Anderson RR. Effect of relaxin on mammary growth in the hypophysectomized rat. Adv Exp Med Biol 1982;143:341-55.
31. Brisken C, Park S, Vass T, Lydon JP, Oâ€™Malley BW, Weinberg RA. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc Natl Acad Sci U S A 1998;95(9):5076-81.
32. Ormandy CJ, Camus A, Barra J, Damotte D, Lucas B, Buteau H, et al. Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev 1997;11(2):167-78.
33. Smith GH, Boulanger CA. Mammary epithelial stem cells: Transplantation and self-renewal analysis. Cell Prolif 2003;36 Suppl 1:3-15.
34. Khaled WT, Read EK, Nicholson SE, Baxter FO, Brennan AJ, Came PJ, et al. The IL-4/IL-13/Stat6 signalling pathway promotes luminal mammary epithelial cell development. Development 2007;134(15):2739-50.
35. Hennighausen L, Robinson GW. Information networks in the mammary gland. Nat Rev Mol Cell Biol 2005;6(9):715-25.
36. Ben-Jonathan N, LaPensee CR, LaPensee EW. What can we learn from rodents about prolactin in humans? Endocr Rev 2008;29(1):1-41.
37. Acosta JJ, Munoz RM, Gonzalez L, Subtil-Rodriguez A, Dominguez-Caceres MA, Garcia-Martinez JM, et al. Src mediates prolactin-dependent proliferation of T47D and MCF7 cells via the activation of focal adhesion kinase/Erk1/2 and phosphatidyl inositol 3-kinase pathways. Mol Endocrinol 2003;17(11):2268-82.
38. Chakravarti P, Henry MK, Quelle FW. Prolactin and heregulin override DNA damage-induced growth arrest and promote phosphatidylinositol-3 kinase-dependent proliferation in breast cancer cells. Int J Oncol 2005;26(2):509-14.
39. Anderson SM, Rudolph MC, McManaman JL, Neville MC. Key stages in mammary gland development. Secretory activation in the mammary gland: Itâ€™s not just about milk protein synthesis! Breast Cancer Res 2007;9(1):204.
40. Chen CC, Stairs DB, Boxer RB, Belka GK, Horseman ND, Alvarez JV, et al. Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways. Genes Dev 2012;26(19):2154-68.
41. Knight CH. Overview of prolactinâ€™s role in farm animal lactation. Livest Prod Sci 2001;70(1-2):87-93.
42. Gorewit RC, Svennersten K, Butler WR, UvnÃ¤s-Moberg K. Endocrine responses in cows milked by hand and machine. J Dairy Sci 1992;75(2):443-8.
43. Peaker M. Autocrine control of milk secretion: Development of the concept. Intercellular Signalling in the Mammary Gland. New York: Plenum Publishing Company; 1995. p. 193-202.
44. Rennison ME, Kerr M, Addey CV, Handel SE, Turner MD, Wilde CJ, et al. Inhibition of constitutive protein secretion from lactating mouse mammary epithelial cells by FIL (feedback inhibitor of lactation), a secreted milk protein. J Cell Sci 1993;106:641-8.
45. Wilde CJ, Knight CH. Metabolic adaptations in mammary gland during the declining phase of lactation. J Dairy Sci 1989;72(6):1679-92.
46. Quarrie LH, Addey CV, Wilde CJ. Local regulation of mammary apoptosis in the lactating goat. Biochem Soc Trans 1994;22(2):178S.
47. Pham K, Dong J, Jiang X, Qu Y, Yu H, Yang Y, et al. Loss of glutaredoxin 3 impedes mammary lobuloalveolar development during pregnancy and lactation. Am J Physiol Endocrinol Metab 2017;312(3):E136-49.
48. Davis KR, Giesy SL, Long Q, Krumm CS, Harvatine KJ, Boisclair YR. XBP1 regulates the biosynthetic capacity of the mammary gland during lactation by controlling epithelial expansion and endoplasmic reticulum formation. Endocrinology 2016;157(1):417-28.
49. Li M, Liu X, Robinson G, Bar-Peled U, Wagner KU, Young WS, et al. Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution. Proc Natl Acad Sci U S A 1997;94(7):3425-30.
50. Marti A, Feng Z, Altermatt HJ, Jaggi R. Milk accumulation triggers apoptosis of mammary epithelial cells. Eur J Cell Biol 1997;73(2):158-65.
51. Lilla JN, Joshi RV, Craik CS, Werb Z. Active plasma kallikrein localizes to mast cells and regulates epithelial cell apoptosis, adipocyte differentiation, and stromal remodeling during mammary gland involution. J Biol Chem 2009;284(20):13792-803.
52. Feinberg TY, Rowe RG, Saunders TL, Weiss SJ. Functional roles of MMP14 and MMP15 in early postnatal mammary gland development. Development 2016;143(21):3956-68.
53. Feng Z, Marti A, Jehn B, Altermatt HJ, Chicaiza G, Jaggi R. Glucocorticoid and progesterone inhibit involution and programmed cell death in the mouse mammary gland. J Cell Biol 1995;131(4):1095-103.
54. Zettl KS, Sjaastad MD, Riskin PM, Parry G, Machen TE, Firestone GL. Glucocorticoid-induced formation of tight junctions in mouse mammary epithelial cells in vitro. Proc Natl Acad Sci U S A 1992;89(19):9069-73.
55. Green KA, Lund LR. ECM degrading proteases and tissue remodelling in the mammary gland. Bioessays 2005;27(9):894-903.
56. Quaglino A, Salierno M, Pellegrotti J, Rubinstein N, Kordon EC. Mechanical strain induces involution-associated events in mammary epithelial cells. BMC Cell Biol 2009;10:55.
57. VanHouten J, Sullivan C, Bazinet C, Ryoo T, Camp R, Rimm DL, et al. PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer. Proc Natl Acad Sci U S A 2010;107(25):11405-10.
58. Kritikou EA, Sharkey A, Abell K, Came PJ, Anderson E, Clarkson RW, et al. A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland. Development 2003;130(15):3459-68.
59. Schere-Levy C, Buggiano V, Quaglino A, Gattelli A, Cirio MC, Piazzon I, et al. Leukemia inhibitory factor induces apoptosis of the mammary epithelial cells and participates in mouse mammary gland involution. Exp Cell Res 2003;282(1):35-47.
60. Matsuda M, Imaoka T, Vomachka AJ, Gudelsky GA, Hou Z, Mistry M, et al. Serotonin regulates mammary gland development via an autocrine-paracrine loop. Dev Cell 2004;6(2):193-203.
61. Nguyen AV, Pollard JW. Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution. Development 2000;127(14):3107-18.
62. Chapman RS, Lourenco PC, Tonner E, Flint DJ, Selbert S, Takeda K, et al. Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. Genes Dev 1999;13(19):2604-16.
63. Humphreys RC, Bierie B, Zhao L, Raz R, Levy D, Hennighausen L. Deletion of Stat3 blocks mammary gland involution and extends functional competence of the secretory epithelium in the absence of lactogenic stimuli. Endocrinology 2002;143(9):3641-50.
64. Baxter FO, Came PJ, Abell K, Kedjouar B, Huth M, Rajewsky K, et al. IKKbeta/2 induces TWEAK and apoptosis in mammary epithelial cells. Development 2006;133:3485-94.
65. Haricharan S, Li Y. STAT signaling in mammary gland differentiation, cell survival and tumorigenesis. Mol Cell Endocrinol 2014;382(1):560-9.
66. Song J, Sapi E, Brown W, Nilsen J, Tartaro K, Kacinski BM, et al. Roles of Fas and Fas ligand during mammary gland remodeling. J Clin Invest 2000;106:1209-20.
67. Sohn BH, Moon HB, Kim TY, Kang HS, Bae YS, Lee KK, et al. Interleukin-10 up-regulates tumour-necrosis-factor-alpha-related apoptosis-inducing ligand (TRAIL) gene expression in mammary epithelial cells at the involution stage. Biochem J 2001;360(17):31-8.
68. Schorr K, Li M, Bar-Peled U, Lewis A, Heredia A, Lewis B, et al. Gain of Bcl-2 is more potent than bax loss in regulating mammary epithelial cell survival in vivo. Cancer Res 1999;59(11):2541-5.
69. Walton KD, Wagner KU, Rucker EB 3rd, Shillingford JM, Miyoshi K, Hennighausen L. Conditional deletion of the bcl-x gene from mouse mammary epithelium results in accelerated apoptosis during involution but does not compromise cell function during lactation. Mech Dev 2001;109(2):281-93.
70. Atabai K, Fernandez R, Huang X, Ueki I, Kline A, Li Y, et al. Mfge8 is critical for mammary gland remodeling during involution. Mol Biol Cell 2005;16(12):5528-37.
71. Hanayama R, Nagata S. Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8. Proc Natl Acad Sci U S A 2005;102(46):16886-91.
72. Seymour T, Twigger AJ, Kakulas F. Pluripotency genes and their functions in the normal and aberrant breast and brain. Int J Mol Sci 2015;16(11):27288-301.
73. Boras-Granic K, Dann P, Wysolmerski JJ. Embryonic cells contribute directly to the quiescent stem cell population in the adult mouse mammary gland. Breast Cancer Res 2014;16(6):487.
74. Hynes NE, Watson CJ. Mammary gland growth factors: Roles in normal development and in cancer. Cold Spring Harb Perspect Biol 2010;2(8):a003186.
75. Schwertfeger KL. Fibroblast growth factors in development and cancer: Insights from the mammary and prostate glands. Curr Drug Targets 2009;10(7):632-44.
76. Kahata K, Maturi V, Moustakas A. TGF-ÃŸ family signaling in ductal differentiation and branching morphogenesis. Cold Spring Harb Perspect Biol 2017. pii: a031997.
77. Mapes J, Li Q, Kannan A, Anandan L, Laws M, Lydon JP, et al. CUZD1 is a critical mediator of the JAK/STAT5 signaling pathway that controls mammary gland development during pregnancy. PLoS Genet 2017;13(3):e1006654.
78. Loladze AV, Stull MA, Rowzee AM, Demarco J, Lantry JH 3rd, Rosen CJ, et al. Epithelial-specific and stage-specific functions of insulin-like growth factor-I during postnatal mammary development. Endocrinology 2006;147(11):5412-23.
79. Schroeder JA, Lee DC. Dynamic expression and activation of ERBB receptors in the developing mouse mammary gland. Cell Growth Differ 1998;9(6):451-64.
80. Watson CJ. Involution: Apoptosis and tissue remodeling that convert the mammary gland from milk factory to a quiescent organ. Breast Cancer Res 2006;8(2):203.
81. Haan C, Kreis S, Margue C, Behrmann I. Jaks and cytokine receptors - An intimate relationship. Biochem Pharmacol 2006;72(11):1538-46.
82. Wilson GJ, Hewit KD, Pallas KJ, Cairney CJ, Lee KM, Hansell CA, et al. Atypical chemokine receptor ACKR2 controls branching morphogenesis in the developing mammary gland. Development 2017;144(1):74-82.
83. Kessenbrock K, Smith P, Steenbeek SC, Pervolarakis N, Kumar R, Minami Y, et al. Diverse regulation of mammary epithelial growth and branching morphogenesis through noncanonical Wnt signaling. Proc Natl Acad Sci U S A 2017;114(12):3121-6.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.