This WIREs title offers downloadable PowerPoint presentations of figures for non-profit,
educational use, provided the content is not modified and full credit is given to the author
References1 Oftedal, OT. The mammary gland and its origin during synapsid evolution. J Mammary Gland Biol Neoplasia 2002, 7:225–252. 2 Balinsky, BI. On the prenatal growth of the mammary gland rudiment in the mouse. J Anat 1950, 84:227–235. 3 Propper, AY. Wandering epithelial cells in the rabbit embryo milk line. A preliminary scanning electron microscope study. Dev Biol 1978, 67:225–231. 4 Howard, BA, Gusterson, BA. Human breast development. J Mammary Gland Biol Neoplasia 2000, 5:119–137. 5 Cunha, GR, Young, P, Christov, K, Guzman, R, Nandi, S, Talamantes, F, Thordarson, G. Mammary phenotypic expression induced in epidermal cells by embryonic mammary mesenchyme. Acta Anat (Basel) 1995, 152:195–204. 6 Kratochwil, K. Organ specificity in mesenchymal induction demonstrated in the embryonic development of the mammary gland of the mouse. Dev Biol 1969, 20:46–71. 7 Sakakura, T, Nishizuka, Y, Dawe, CJ. Mesenchyme‐dependent morphogenesis and epithelium‐specific cytodifferentiation in mouse mammary gland. Science 1976, 194:1439–1441. 8 Robinson, GW, Karpf, AB, Kratochwil, K. Regulation of mammary gland development by tissue interaction. J Mammary Gland Biol Neoplasia 1999, 4:9–19. 9 Sakakura, T, Sakagami, Y, Nishizuka, Y. Dual origin of mesenchymal tissues participating in mouse mammary gland embryogenesis. Dev Biol 1982, 91:202–207. 10 Chu, EY, Hens, J, Andl, T, Kairo, A, Yamaguchi, TP, Brisken, C, Glick, A, Wysolmerski, JJ, Millar, SE. Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development 2004, 131:4819–4829. 11 Veltmaat, JM, Van Veelen, W, Thiery, JP, Bellusci, S. Identification of the mammary line in mouse by Wnt10b expression. Dev Dyn 2004, 229:349–356. 12 van Genderen, C, Okamura, RM, Farinas, I, Quo, RG, Parslow, TG, Bruhn, L, Grosschedl, R. Development of several organs that require inductive epithelial‐mesenchymal interactions is impaired in LEF‐1‐deficient mice. Genes Dev 1994, 8:2691–2703. 13 Jerome‐Majewska, LA, Jenkins, GP, Ernstoff, E, Zindy, F, Sherr, CJ, Papaioannou, VE. Tbx3, the ulnar‐mammary syndrome gene, and Tbx2 interact in mammary gland development through a p19Arf/p53‐independent pathway. Dev Dyn 2005, 234:922–933. 14 Bamshad, M, Lin, RC, Law, DJ, Watkins, WC, Krakowiak, PA, Moore, ME, Franceschini, P, Lala, R, Holmes, LB, Gebuhr, TC, et al. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar‐mammary syndrome. Nat Genet 1997, 16:311–315. 15 Cho, KW, Kim, JY, Song, SJ, Farrell, E, Eblaghie, MC, Kim, HJ, Tickle, C, Jung, HS. Molecular interactions between Tbx3 and Bmp4 and a model for dorsoventral positioning of mammary gland development. Proc Natl Acad Sci U S A 2006, 103:16788–16793. 16 Davenport, TG, Jerome‐Majewska, LA, Papaioannou, VE. Mammary gland, limb and yolk sac defects in mice lacking Tbx3, the gene mutated in human ulnar mammary syndrome. Development 2003, 130:2263–2273. 17 Veltmaat, JM, Relaix, F, Le, LT, Kratochwil, K, Sala, FG, van Veelen, W, Rice, R, Spencer‐Dene, B, Mailleux, AA, Rice, DP, et al. Gli3‐mediated somitic Fgf10 expression gradients are required for the induction and patterning of mammary epithelium along the embryonic axes. Development 2006, 133:2325–2335. 18 Mailleux, AA, Kelly, R, Veltmaat, JM, De Langhe, SP, Zaffran, S, Thiery, JP, Bellusci, S. Fgf10 expression identifies parabronchial smooth muscle cell progenitors and is required for their entry into the smooth muscle cell lineage. Development 2005, 132:2157–2166. 19 Baban, A, Torre, M, Bianca, S, Buluggiu, A, Rossello, MI, Calevo, MG, Valle, M, Ravazzolo, R, Jasonni, V, Lerone, M. Poland syndrome with bilateral features: case description with review of the literature. Am J Med Genet A 2009, 149A:1597–1602. 20 Hatsell, SJ, Cowin, P. Gli3‐mediated repression of Hedgehog targets is required for normal mammary development. Development 2006, 133:3661–3670. 21 Wang, C, Ruther, U, Wang, B. The Shh‐independent activator function of the full‐length Gli3 protein and its role in vertebrate limb digit patterning. Dev Biol 2007, 305:460–469. 22 Aoto, K, Nishimura, T, Eto, K, Motoyama, J. Mouse GLI3 regulates Fgf8 expression and apoptosis in the developing neural tube, face, and limb bud. Dev Biol 2002, 251:320–332. 23 Panchal, H, Wansbury, O, Parry, S, Ashworth, A, Howard, B. Neuregulin3 alters cell fate in the epidermis and mammary gland. BMC Dev Biol 2007, 7:105. 24 Howard, BA, Gusterson, BA. The characterization of a mouse mutant that displays abnormal mammary gland development. Mamm Genome 2000, 11:234–237. 25 Howard, B, Panchal, H, McCarthy, A, Ashworth, A. Identification of the scaramanga gene implicates Neuregulin3 in mammary gland specification. Genes Dev 2005, 19:2078–2090. 26 Eblaghie, MC, Song, SJ, Kim, JY, Akita, K, Tickle, C, Jung, HS. Interactions between FGF and Wnt signals and Tbx3 gene expression in mammary gland initiation in mouse embryos. J Anat 2004, 205:1–13. 27 Fliniaux, I, Mikkola, ML, Lefebvre, S, Thesleff, I. Identification of dkk4 as a target of Eda‐A1/Edar pathway reveals an unexpected role of ectodysplasin as inhibitor of Wnt signalling in ectodermal placodes. Dev Biol 2008, 320:60–71. 28 Mustonen, T, Pispa, J, Mikkola, ML, Pummila, M, Kangas, AT, Pakkasjarvi, L, Jaatinen, R, Thesleff, I. Stimulation of ectodermal organ development by Ectodysplasin‐A1. Dev Biol 2003, 259:123–136. 29 Monreal, AW, Ferguson, BM, Headon, DJ, Street, SL, Overbeek, PA, Zonana, J. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet 1999, 22:366–369. 30 Cowin, P, Wysolmerski, J. Molecular mechanisms guiding embryonic mammary gland development. Cold Spring Harb Perspect Biol 2010, 2:a003251. 31 Hogg, NA, Harrison, CJ, Tickle, C. Lumen formation in the developing mouse mammary gland. J Embryol Exp Morphol 1983, 73:39–57. 32 Blatchford, DR, Quarrie, LH, Tonner, E, McCarthy, C, Flint, DJ, Wilde, CJ. Influence of microenvironment on mammary epithelial cell survival in primary culture. J Cell Physiol 1999, 181:304–311. 33 Ewald, AJ, Brenot, A, Duong, M, Chan, BS, Werb, Z. Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis. Dev Cell 2008, 14:570–581. 34 Debnath, J, Mills, KR, Collins, NL, Reginato, MJ, Muthuswamy, SK, Brugge, JS. The role of apoptosis in creating and maintaining luminal space within normal and oncogene‐expressing mammary acini. Cell 2002, 111:29–40. 35 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, 134:1221–1230. 36 Kratochwil, K, Schwartz, P. Tissue interaction in androgen response of embryonic mammary rudiment of mouse: identification of target tissue for testosterone. Proc Natl Acad Sci U S A 1976, 73:4041–4044. 37 Juppner, H, Abou‐Samra, AB, Freeman, M, Kong, XF, Schipani, E, Richards, J, Kolakowski, LF Jr. Hock, J, Potts, JT Jr. Kronenberg, HM, et al. A G protein‐linked receptor for parathyroid hormone and parathyroid hormone‐related peptide. Science 1991, 254:1024–1026. 38 Wysolmerski, JJ, McCaughern‐Carucci, JF, Daifotis, AG, Broadus, AE, Philbrick, WM. Overexpression of parathyroid hormone‐related protein or parathyroid hormone in transgenic mice impairs branching morphogenesis during mammary gland development. Development 1995, 121:3539–3547. 39 Jobert, AS, Zhang, P, Couvineau, A, Bonaventure, J, Roume, J, Le Merrer, M, Silve, C. Absence of functional receptors for parathyroid hormone and parathyroid hormone‐related peptide in Blomstrand chondrodysplasia. J Clin Invest 1998, 102:34–40. 40 Wysolmerski, JJ, Cormier, S, Philbrick, WM, Dann, P, Zhang, JP, Roume, J, Delezoide, AL, Silve, C. Absence of functional type 1 parathyroid hormone (PTH)/PTH‐related protein receptors in humans is associated with abnormal breast development and tooth impaction. J Clin Endocrinol Metab 2001, 86:1788–1794. 41 Wysolmerski, JJ, Philbrick, WM, Dunbar, ME, Lanske, B, Kronenberg, H, Broadus, AE. Rescue of the parathyroid hormone‐related protein knockout mouse demonstrates that parathyroid hormone‐related protein is essential for mammary gland development. Development 1998, 125:1285–1294. 42 Foley, J, Dann, P, Hong, J, Cosgrove, J, Dreyer, B, Rimm, D, Dunbar, M, Philbrick, W, Wysolmerski, J. Parathyroid hormone‐related protein maintains mammary epithelial fate and triggers nipple skin differentiation during embryonic breast development. Development 2001, 128:513–525. 43 Williams, JM, Daniel, CW. Mammary ductal elongation: differentiation of myoepithelium and basal lamina during branching morphogenesis. Dev Biol 1983, 97:274–290. 44 Trott, JF, Vonderhaar, BK, Hovey, RC. Historical perspectives of prolactin and growth hormone as mammogens, lactogens and galactagogues—agog for the future! J Mammary Gland Biol Neoplasia 2008, 13:3–11. 45 Gallego, MI, Binart, N, Robinson, GW, Okagaki, R, Coschigano, KT, Perry, J, Kopchick, JJ, Oka, T, Kelly, PA, Hennighausen, L. Prolactin, growth hormone, and epidermal growth factor activate Stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects. Dev Biol 2001, 229:163–175. 46 Ruan, W, Kleinberg, DL. Insulin‐like growth factor I is essential for terminal end bud formation and ductal morphogenesis during mammary development. Endocrinology 1999, 140:5075–5081. 47 Zhou, Y, Xu, BC, Maheshwari, HG, He, L, Reed, M, Lozykowski, M, Okada, S, Cataldo, L, Coschigamo, K, Wagner, TE, et al. A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci U S A 1997, 94:13215–13220. 48 Richards, RG, Klotz, DM, Walker, MP, Diaugustine, RP. Mammary gland branching morphogenesis is diminished in mice with a deficiency of insulin‐like growth factor‐I (IGF‐I), but not in mice with a liver‐specific deletion of IGF‐I. Endocrinology 2004, 145:3106–3110. 49 Cannata, D, Lann, D, Wu, Y, Elis, S, Sun, H, Yakar, S, Lazzarino, DA, Wood, TL, Leroith, D. Elevated circulating IGF‐I promotes mammary gland development and proliferation. Endocrinology 2010, 151:5751–5761. 50 Bohlke, K, Cramer, DW, Trichopoulos, D, Mantzoros, CS. Insulin‐like growth factor‐I in relation to premenopausal ductal carcinoma in situ of the breast. Epidemiology 1998, 9:570–573. 51 Hankinson, SE, Willett, WC, Colditz, GA, Hunter, DJ, Michaud, DS, Deroo, B, Rosner, B, Speizer, FE, Pollak, M. Circulating concentrations of insulin‐like growth factor‐I and risk of breast cancer. Lancet 1998, 351:1393–1396. 52 Lieberman, ME, Maurer, RA, Gorski, J. Estrogen control of prolactin synthesis in vitro. Proc Natl Acad Sci U S A 1978, 75:5946–5949. 53 Silberstein, GB, Daniel, CW. Elvax 40P implants: sustained, local release of bioactive molecules influencing mammary ductal development. Dev Biol 1982, 93:272–278. 54 Daniel, CW, Silberstein, GB, Strickland, P. Direct action of 17 β‐estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography. Cancer Res 1987, 47:6052–6057. 55 Silberstein, GB, Van Horn, K, Shyamala, G, Daniel, CW. Essential role of endogenous estrogen in directly stimulating mammary growth demonstrated by implants containing pure antiestrogens. Endocrinology 1994, 134:84–90. 56 Lubahn, DB, Moyer, JS, Golding, TS, Couse, JF, Korach, KS, Smithies, O. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci U S A 1993, 90:11162–11166. 57 Krege, JH, Hodgin, JB, Couse, JF, Enmark, E, Warner, M, Mahler, JF, Sar, M, Korach, KS, Gustafsson, JA, Smithies, O. Generation and reproductive phenotypes of mice lacking estrogen receptor β. Proc Natl Acad Sci U S A 1998, 95:15677–15682. 58 Zeps, N, Bentel, JM, Papadimitriou, JM, D`Antuono, MF, Dawkins, HJ. Estrogen receptor‐negative epithelial cells in mouse mammary gland development and growth. Differentiation 1998, 62:221–226. 59 Mallepell, S, Krust, A, Chambon, P, Brisken, C. Paracrine signaling through the epithelial estrogen receptor α is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci U S A 2006, 103:2196–2201. 60 Nandi, S. Endocrine control of mammary‐gland development and function in the C3H/He Crgl mouse. J Natl Cancer Inst Monogr 1958, 21:1039–1063. 61 Nandi, S. Hormonal control of mammogenesis and lactogenesis in the C3H/He Crgl mouse. Univ Calif Berkeley Publ Zoo 1959, 65:1–128. 62 Feng, Y, Manka, D, Wagner, KU, Khan, SA. Estrogen receptor‐ α expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice. Proc Natl Acad Sci U S A 2007, 104:14718–14723. 63 Coleman, S, Silberstein, GB, Daniel, CW. Ductal morphogenesis in the mouse mammary gland: evidence supporting a role for epidermal growth factor. Dev Biol 1988, 127:304–315. 64 Kenney, NJ, Bowman, A, Korach, KS, Barrett, JC, Salomon, DS. Effect of exogenous epidermal‐like growth factors on mammary gland development and differentiation in the estrogen receptor‐ α knockout (ERKO) mouse. Breast Cancer Res Treat 2003, 79:161–173. 65 Luetteke, NC, Qiu, TH, Fenton, SE, Troyer, KL, Riedel, RF, Chang, A, Lee, DC. Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development 1999, 126:2739–2750. 66 Ciarloni, L, Mallepell, S, Brisken, C. Amphiregulin is an essential mediator of estrogen receptor α function in mammary gland development. Proc Natl Acad Sci U S A 2007, 104:5455–5460. 67 Sternlicht, MD, Sunnarborg, SW, Kouros‐Mehr, H, Yu, Y, Lee, DC, Werb, Z. Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17‐dependent shedding of epithelial amphiregulin. Development 2005, 132:3923–3933. 68 Wiesen, JF, Young, P, Werb, Z, Cunha, GR. Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development. Development 1999, 126:335–344. 69 Chakravorti, S, Sheffield, L. Acidic and basic fibroblast growth factor mRNA and protein in mouse mammary glands. Endocrine 1996, 4:175–182. 70 Lu, P, Ewald, AJ, Martin, GR, Werb, Z. Genetic mosaic analysis reveals FGF receptor 2 function in terminal end buds during mammary gland branching morphogenesis. Dev Biol 2008, 321:77–87. 71 Silberstein, GB, Daniel, CW. Reversible inhibition of mammary gland growth by transforming growth factor‐ β. Science 1987, 237:291–293. 72 Ewan, KB, Shyamala, G, Ravani, SA, Tang, Y, Akhurst, R, Wakefield, L, Barcellos‐Hoff, MH. Latent transforming growth factor‐ β activation in mammary gland: regulation by ovarian hormones affects ductal and alveolar proliferation. Am J Pathol 2002, 160:2081–2093. 73 Ingman, WV, Robertson, SA. Mammary gland development in transforming growth factor β1 mutant mice: systemic and epithelial effects. Biol Reprod 2008, 79:711–717. 74 Joseph, H, Gorska, AE, Sohn, P, Moses, HL, Serra, R. Overexpression of a kinase‐deficient transforming growth factor‐ β type II receptor in mouse mammary stroma results in increased epithelial branching. Mol Biol Cell 1999, 10:1221–1234. 75 Cheng, N, Bhowmick, NA, Chytil, A, Gorksa, AE, Brown, KA, Muraoka, R, Arteaga, CL, Neilson, EG, Hayward, SW, Moses, HL. Loss of TGF‐ β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF‐ α‐, MSP‐ and HGF‐mediated signaling networks. Oncogene 2005, 24:5053–5068. 76 Gorska, AE, Joseph, H, Derynck, R, Moses, HL, Serra, R. Dominant‐negative interference of the transforming growth factor β type II receptor in mammary gland epithelium results in alveolar hyperplasia and differentiation in virgin mice. Cell Growth Differ 1998, 9:229–238. 77 Nelson, CM, Vanduijn, MM, Inman, JL, Fletcher, DA, Bissell, MJ. Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures. Science 2006, 314:298–300. 78 Roarty, K, Serra, R. Wnt5a is required for proper mammary gland development and TGF‐ β‐mediated inhibition of ductal growth. Development 2007, 134:3929–3939. 79 Srinivasan, K, Strickland, P, Valdes, A, Shin, GC, Hinck, L. Netrin‐1/neogenin interaction stabilizes multipotent progenitor cap cells during mammary gland morphogenesis. Dev Cell 2003, 4:371–382. 80 Strickland, P, Shin, GC, Plump, A, Tessier‐Lavigne, M, Hinck, L. Slit2 and netrin 1 act synergistically as adhesive cues to generate tubular bi‐layers during ductal morphogenesis. Development 2006, 133:823–832. 81 Khialeeva, E, Lane, TF, Carpenter, EM. Disruption of reelin signaling alters mammary gland morphogenesis. Development 2011, 138:767–776. 82 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, 104:2715–2720. 83 Atabai, K, Fernandez, R, Huang, X, Ueki, I, Kline, A, Li, Y, Sadatmansoori, S, Smith‐Steinhart, C, Zhu, W, Pytela, R, et al. Mfge8 is critical for mammary gland remodeling during involution. Mol Biol Cell 2005, 16:5528–5537. 84 Lee, S, Medina, D, Tsimelzon, A, Mohsin, SK, Mao, S, Wu, Y, Allred, DC. Alterations of gene expression in the development of early hyperplastic precursors of breast cancer. Am J Pathol 2007, 171:252–262. 85 Baillo, A, Giroux, C, Ethier, SP. Knock‐down of amphiregulin inhibits cellular invasion in inflammatory breast cancer. J Cell Physiol 2011. 86 Djonov, V, Andres, AC, Ziemiecki, A. Vascular remodelling during the normal and malignant life cycle of the mammary gland. Microsc Res Tech 2001, 52:182–189. 87 Lydon, JP, DeMayo, FJ, Funk, CR, Mani, SK, Hughes, AR, Montgomery, CA Jr, Shyamala, G, Conneely, OM, O`Malley, BW. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 1995, 9:2266–2278. 88 Brisken, C, Park, S, Vass, T, Lydon, JP, O`Malley, BW, Weinberg, RA. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc Natl Acad Sci U S A 1998, 95:5076–5081. 89 Seagroves, TN, Lydon, JP, Hovey, RC, Vonderhaar, BK, Rosen, JM. C/EBP β (CCAAT/enhancer binding protein) controls cell fate determination during mammary gland development. Mol Endocrinol 2000, 14:359–368. 90 Shyamala, G, Schneider, W, Schott, D. Developmental regulation of murine mammary progesterone receptor gene expression. Endocrinology 1990, 126:2882–2889. 91 Mulac‐Jericevic, B, Lydon, JP, DeMayo, FJ, Conneely, OM. Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci U S A 2003, 100:9744–9749. 92 Mulac‐Jericevic, B, Mullinax, RA, DeMayo, FJ, Lydon, JP, Conneely, OM. Subgroup of reproductive functions of progesterone mediated by progesterone receptor‐B isoform. Science 2000, 289:1751–1754. 93 Richer, JK, Jacobsen, BM, Manning, NG, Abel, MG, Wolf, DM, Horwitz, KB. Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem 2002, 277:5209–5218. 94 Graham, JD, Yeates, C, Balleine, RL, Harvey, SS, Milliken, JS, Bilous, AM, Clarke, CL. Characterization of progesterone receptor A and B expression in human breast cancer. Cancer Res 1995, 55:5063–5068. 95 Fata, JE, Kong, YY, Li, J, Sasaki, T, Irie‐Sasaki, J, Moorehead, RA, Elliott, R, Scully, S, Voura, EB, Lacey, DL, et al. The osteoclast differentiation factor osteoprotegerin‐ligand is essential for mammary gland development. Cell 2000, 103:41–50. 96 Beleut, M, Rajaram, RD, Caikovski, M, Ayyanan, A, Germano, D, Choi, Y, Schneider, P, Brisken, C. Two distinct mechanisms underlie progesterone‐induced proliferation in the mammary gland. Proc Natl Acad Sci U S A 2010, 107:2989–2994. 97 Mukherjee, A, Soyal, SM, Li, J, Ying, Y, He, B, DeMayo, FJ, Lydon, JP. Targeting RANKL to a specific subset of murine mammary epithelial cells induces ordered branching morphogenesis and alveologenesis in the absence of progesterone receptor expression. FASEB J 2010, 24:4408–4419. 98 Fernandez‐Valdivia, R, Mukherjee, A, Creighton, CJ, Buser, AC, DeMayo, FJ, Edwards, DP, Lydon, JP. Transcriptional response of the murine mammary gland to acute progesterone exposure. Endocrinology 2008, 149:6236–6250. 99 Schramek, D, Leibbrandt, A, Sigl, V, Kenner, L, Pospisilik, JA, Lee, HJ, Hanada, R, Joshi, PA, Aliprantis, A, Glimcher, L, et al. Osteoclast differentiation factor RANKL controls development of progestin‐driven mammary cancer. Nature 2010, 468:98–102. 100 Gonzalez‐Suarez, E, Jacob, AP, Jones, J, Miller, R, Roudier‐Meyer, MP, Erwert, R, Pinkas, J, Branstetter, D, Dougall, WC. RANK ligand mediates progestin‐induced mammary epithelial proliferation and carcinogenesis. Nature 2010, 468:103–107. 101 Ormandy, CJ, Camus, A, Barra, J, Damotte, D, Lucas, B, Buteau, H, Edery, M, Brousse, N, Babinet, C, Binart, N, et al. Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev 1997, 11:167–178. 102 Horseman, ND, Zhao, W, Montecino‐Rodriguez, E, Tanaka, M, Nakashima, K, Engle, SJ, Smith, F, Markoff, E, Dorshkind, K. Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene. EMBO J 1997, 16:6926–6935. 103 Naylor, MJ, Lockefeer, JA, Horseman, ND, Ormandy, CJ. Prolactin regulates mammary epithelial cell proliferation via autocrine/paracrine mechanism. Endocrine 2003, 20:111–114. 104 Brisken, C, Kaur, S, Chavarria, TE, Binart, N, Sutherland, RL, Weinberg, RA, Kelly, PA, Ormandy, CJ. Prolactin controls mammary gland development via direct and indirect mechanisms. Dev Biol 1999, 210:96–106. 105 Vomachka, AJ, Pratt, SL, Lockefeer, JA, Horseman, ND. Prolactin gene‐disruption arrests mammary gland development and retards T‐antigen‐induced tumor growth. Oncogene 2000, 19:1077–1084. 106 Han, Y, Watling, D, Rogers, NC, Stark, GR. JAK2 and STAT5, but not JAK1 and STAT1, are required for prolactin‐induced β‐lactoglobulin transcription. Mol Endocrinol 1997, 11:1180–1188. 107 Cui, Y, Riedlinger, G, Miyoshi, K, Tang, W, Li, C, Deng, CX, Robinson, GW, Hennighausen, L. Inactivation of Stat5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol Cell Biol 2004, 24:8037–8047. 108 Wagner, KU, Krempler, A, Triplett, AA, Qi, Y, George, NM, Zhu, J, Rui, H. Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice. Mol Cell Biol 2004, 24:5510–5520. 109 Naylor, MJ, Li, N, Cheung, J, Lowe, ET, Lambert, E, Marlow, R, Wang, P, Schatzmann, F, Wintermantel, T, Schuetz, G, et al. Ablation of β1 integrin in mammary epithelium reveals a key role for integrin in glandular morphogenesis and differentiation. J Cell Biol 2005, 171:717–728. 110 Galbaugh, T, Feeney, YB, Clevenger, CV. Prolactin receptor‐integrin cross‐talk mediated by SIRP α in breast cancer cells. Mol Cancer Res 2010, 8:1413–1424. 111 Srivastava, S, Matsuda, M, Hou, Z, Bailey, JP, Kitazawa, R, Herbst, MP, Horseman, ND. Receptor activator of NF‐ κB ligand induction via Jak2 and Stat5a in mammary epithelial cells. J Biol Chem 2003, 278:46171–46178. 112 Fernandez‐Valdivia, R, Mukherjee, A, Ying, Y, Li, J, Paquet, M, DeMayo, FJ, Lydon, JP. The RANKL signaling axis is sufficient to elicit ductal side‐branching and alveologenesis in the mammary gland of the virgin mouse. Dev Biol 2009, 328:127–139. 113 Oakes, SR, Rogers, RL, Naylor, MJ, Ormandy, CJ. Prolactin regulation of mammary gland development. J Mammary Gland Biol Neoplasia 2008, 13:13–28. 114 D`Cruz, CM, Moody, SE, Master, SR, Hartman, JL, Keiper, EA, Imielinski, MB, Cox, JD, Wang, JY, Ha, SI, Keister, BA, et al. Persistent parity‐induced changes in growth factors, TGF‐ β3, and differentiation in the rodent mammary gland. Mol Endocrinol 2002, 16:2034–2051. 115 Balogh, GA, Heulings, R, Mailo, DA, Russo, PA, Sheriff, F, Russo, IH, Moral, R, Russo, J. Genomic signature induced by pregnancy in the human breast. Int J Oncol 2006, 28:399–410. 116 Li, M, Liu, X, Robinson, G, Bar‐Peled, U, Wagner, KU, Young, WS, Hennighausen, L, Furth, PA. Mammary‐derived signals activate programmed cell death during the first stage of mammary gland involution. Proc Natl Acad Sci U S A 1997, 94:3425–3430. 117 Marti, A, Feng, Z, Altermatt, HJ, Jaggi, R. Milk accumulation triggers apoptosis of mammary epithelial cells. Eur J Cell Biol 1997, 73:158–165. 118 Marti, A, Ritter, PM, Jager, R, Lazar, H, Baltzer, A, Schenkel, J, Declercq, W, Vandenabeele, P, Jaggi, R. Mouse mammary gland involution is associated with cytochrome c release and caspase activation. Mech Dev 2001, 104:89–98. 119 Song, J, Sapi, E, Brown, W, Nilsen, J, Tartaro, K, Kacinski, BM, Craft, J, Naftolin, F, Mor, G. Roles of Fas and Fas ligand during mammary gland remodeling. J Clin Invest 2000, 106:1209–1220. 120 Baxter, FO, Came, PJ, Abell, K, Kedjouar, B, Huth, M, Rajewsky, K, Pasparakis, M, Watson, CJ. IKK β/2 induces TWEAK and apoptosis in mammary epithelial cells. Development 2006, 133:3485–3494. 121 Kreuzaler, PA, Staniszewska, AD, Li, W, Omidvar, N, Kedjouar, B, Turkson, J, Poli, V, Flavell, RA, Clarkson, RW, Watson, CJ. Stat3 controls lysosomal‐mediated cell death in vivo. Nat Cell Biol 2011. 122 Creamer, BA, Sakamoto, K, Schmidt, JW, Triplett, AA, Moriggl, R, Wagner, KU. Stat5 promotes survival of mammary epithelial cells through transcriptional activation of a distinct promoter in Akt1. Mol Cell Biol 2010, 30:2957–2970. 123 Schwertfeger, KL, Richert, MM, Anderson, SM. Mammary gland involution is delayed by activated Akt in transgenic mice. Mol Endocrinol 2001, 15:867–881. 124 Maroulakou, IG, Oemler, W, Naber, SP, Klebba, I, Kuperwasser, C, Tsichlis, PN. Distinct roles of the three Akt isoforms in lactogenic differentiation and involution. J Cell Physiol 2008, 217:468–477. 125 Clarkson, RW, Boland, MP, Kritikou, EA, Lee, JM, Freeman, TC, Tiffen, PG, Watson, CJ. The genes induced by signal transducer and activators of transcription (STAT)3 and STAT5 in mammary epithelial cells define the roles of these STATs in mammary development. Mol Endocrinol 2006, 20:675–685. 126 Chapman, RS, Lourenco, PC, Tonner, E, Flint, DJ, Selbert, S, Takeda, K, Akira, S, Clarke, AR, Watson, CJ. Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. Genes Dev 1999, 13:2604–2616. 127 Kritikou, EA, Sharkey, A, Abell, K, Came, PJ, Anderson, E, Clarkson, RW, Watson, CJ. A dual, non‐redundant, role for LIF as a regulator of development and STAT3‐mediated cell death in mammary gland. Development 2003, 130:3459–3468. 128 Abell, K, Bilancio, A, Clarkson, RW, Tiffen, PG, Altaparmakov, AI, Burdon, TG, Asano, T, Vanhaesebroeck, B, Watson, CJ. Stat3‐induced apoptosis requires a molecular switch in PI(3)K subunit composition. Nat Cell Biol 2005, 7:392–398. 129 Tonner, E, Barber, MC, Travers, MT, Logan, A, Flint, DJ. Hormonal control of insulin‐like growth factor‐binding protein‐5 production in the involuting mammary gland of the rat. Endocrinology 1997, 138:5101–5107. 130 Ning, Y, Hoang, B, Schuller, AG, Cominski, TP, Hsu, MS, Wood, TL, Pintar, JE. Delayed mammary gland involution in mice with mutation of the insulin‐like growth factor binding protein 5 gene. Endocrinology 2007, 148:2138–2147. 131 Lund, LR, Bjorn, SF, Sternlicht, MD, Nielsen, BS, Solberg, H, Usher, PA, Osterby, R, Christensen, IJ, Stephens, RW, Bugge, TH, et al. Lactational competence and involution of the mouse mammary gland require plasminogen. Development 2000, 127:4481–4492. 132 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, 284:13792–13803. 133 Sympson, CJ, Talhouk, RS, Alexander, CM, Chin, JR, Clift, SM, Bissell, MJ, Werb, Z. Targeted expression of stromelysin‐1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue‐specific gene expression. J Cell Biol 1994, 125:681–693. 134 Fata, JE, Leco, KJ, Voura, EB, Yu, HY, Waterhouse, P, Murphy, G, Moorehead, RA, Khokha, R. Accelerated apoptosis in the Timp‐3‐deficient mammary gland. J Clin Invest 2001, 108:831–841. 135 Witty, JP, Wright, JH, Matrisian, LM. Matrix metalloproteinases are expressed during ductal and alveolar mammary morphogenesis, and misregulation of stromelysin‐1 in transgenic mice induces unscheduled alveolar development. Mol Biol Cell 1995, 6:1287–1303. 136 Wiseman, BS, Sternlicht, MD, Lund, LR, Alexander, CM, Mott, J, Bissell, MJ, Soloway, P, Itohara, S, Werb, Z. Site‐specific inductive and inhibitory activities of MMP‐2 and MMP‐3 orchestrate mammary gland branching morphogenesis. J Cell Biol 2003, 162:1123–1133. 137 Clarkson, RW, Watson, CJ. Microarray analysis of the involution switch. J Mammary Gland Biol Neoplasia 2003, 8:309–319. 138 Schedin, P. Pregnancy‐associated breast cancer and metastasis. Nat Rev Cancer 2006, 6:281–291. 139 Bemis, LT, Schedin, P. Reproductive state of rat mammary gland stroma modulates human breast cancer cell migration and invasion. Cancer Res 2000, 60:3414–3418. 140 McDaniel, SM, Rumer, KK, Biroc, SL, Metz, RP, Singh, M, Porter, W, Schedin, P. Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. Am J Pathol 2006, 168:608–620. 141 Ghosh, K, Hartmann, LC, Reynolds, C, Visscher, DW, Brandt, KR, Vierkant, RA, Scott, CG, Radisky, DC, Sellers, TA, Pankratz, VS, et al. Association between mammographic density and age‐related lobular involution of the breast. J Clin Oncol 2010, 28:2207–2212. 142 Milanese, TR, Hartmann, LC, Sellers, TA, Frost, MH, Vierkant, RA, Maloney, SD, Pankratz, VS, Degnim, AC, Vachon, CM, Reynolds, CA, et al. Age‐related lobular involution and risk of breast cancer. J Natl Cancer Inst 2006, 98:1600–1607. 143 Daniel, CW, De Ome, KB, Young, JT, Blair, PB, Faulkin, LJ Jr. The in vivo life span of normal and preneoplastic mouse mammary glands: a serial transplantation study. Proc Natl Acad Sci U S A 1968, 61:53–60. 144 Daniel, CW, Young, LJ, Medina, D, DeOme, KB. The influence of mammogenic hormones on serially transplanted mouse mammary gland. Exp Gerontol 1971, 6:95–101. 145 Young, LJ, Medina, D, DeOme, KB, Daniel, CW. The influence of host and tissue age on life span and growth rate of serially transplanted mouse mammary gland. Exp Gerontol 1971, 6:49–56. 146 Shackleton, M, Vaillant, F, Simpson, KJ, Stingl, J, Smyth, GK, Asselin‐Labat, ML, Wu, L, Lindeman, GJ, Visvader, JE. Generation of a functional mammary gland from a single stem cell. Nature 2006, 439:84–88. 147 Stingl, J, Eirew, P, Ricketson, I, Shackleton, M, Vaillant, F, Choi, D, Li, HI, Eaves, CJ. Purification and unique properties of mammary epithelial stem cells. Nature 2006, 439:993–997. 148 Stingl, J, Eaves, CJ, Zandieh, I, Emerman, JT. Characterization of bipotent mammary epithelial progenitor cells in normal adult human breast tissue. Breast Cancer Res Treat 2001, 67:93–109. 149 Clarke, RB. Isolation and characterization of human mammary stem cells. Cell Prolif 2005, 38:375–386. 150 Chepko, G, Smith, GH. Three division‐competent, structurally‐distinct cell populations contribute to murine mammary epithelial renewal. Tissue Cell 1997, 29:239–253. 151 Kordon, EC, Smith, GH. An entire functional mammary gland may comprise the progeny from a single cell. Development 1998, 125:1921–1930. 152 Moraes, RC, Zhang, X, Harrington, N, Fung, JY, Wu, MF, Hilsenbeck, SG, Allred, DC, Lewis, MT. Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia. Development 2007, 134:1231–1242. 153 Asselin‐Labat, ML, Sutherland, KD, Barker, H, Thomas, R, Shackleton, M, Forrest, NC, Hartley, L, Robb, L, Grosveld, FG, van der Wees, J, et al. Gata‐3 is an essential regulator of mammary‐gland morphogenesis and luminal‐cell differentiation. Nat Cell Biol 2007, 9:201–209. 154 Booth, BW, Boulanger, CA, Smith, GH. Alveolar progenitor cells develop in mouse mammary glands independent of pregnancy and lactation. J Cell Physiol 2007, 212:729–736. 155 Knoblich, JA. Asymmetric cell division: recent developments and their implications for tumour biology. Nat Rev Mol Cell Biol 2010, 11:849–860. 156 Smith, GH, Medina, D. A morphologically distinct candidate for an epithelial stem cell in mouse mammary gland. J Cell Sci 1988, 90(Pt 1):173–183. 157 Daniel, CW, Young, LJ. Influence of cell division on an aging process. Life span of mouse mammary epithelium during serial propagation in vivo. Exp Cell Res 1971, 65:27–32. 158 Fernandez‐Gonzalez, R, Illa‐Bochaca, I, Welm, BE, Fleisch, MC, Werb, Z, Ortiz‐de‐Solorzano, C, Barcellos‐Hoff, MH. Mapping mammary gland architecture using multi‐scale in situ analysis. Integr Biol (Camb) 2009, 1:80–89. 159 Farnie, G, Clarke, RB. Mammary stem cells and breast cancer—role of Notch signalling. Stem Cell Rev 2007, 3:169–175. 160 Visbal, AP, Lewis, MT. Hedgehog signaling in the normal and neoplastic mammary gland. Curr Drug Targets 2010, 11:1103–1111. 161 Wend, P, Holland, JD, Ziebold, U, Birchmeier, W. Wnt signaling in stem and cancer stem cells. Semin Cell Dev Biol 2010, 21:855–863. 162 Perou, CM, Sorlie, T, Eisen, MB, van de Rijn, M, Jeffrey, SS, Rees, CA, Pollack, JR. Ross, DT, Johnsen, H, Akslen, LA, et al. Molecular portraits of human breast tumours. Nature 2000, 406:747–752. 163 Al‐Hajj, M, Wicha, MS, Benito‐Hernandez, A, Morrison, SJ, Clarke, MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003, 100:3983–3988. 164 Bonnet, D, Dick, JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997, 3:730–737. 165 Visvader, JE. Cells of origin in cancer. Nature 2011, 469:314–322. 166 Lim, E, Vaillant, F, Wu, D, Forrest, NC, Pal, B, Hart, AH, Asselin‐Labat, ML, Gyorki, DE, Ward, T, Partanen, A, et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 2009, 15:907–913. 167 Li, X, Lewis, MT, Huang, J, Gutierrez, C, Osborne, CK, Wu, MF, Hilsenbeck, SG, Pavlick, A, Zhang, X, Chamness, GC, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 2008, 100:672–679.