18. Pufe T, Bartscher M, Petersen W, Tillmann B, Mentlein R (2003) Pleiotrophin, an embryonic differentiation and growth factor, is expressed in osteoarthritis. Osteoarthritis Cartilage 11: 260–264. 19. Fang W, Hartmann N, Chow DT, Riegel AT, Wellstein A (1992) Pleiotrophin stimulates fibroblasts and endothelial and epithelial cells and is expressed in human cancer. J Biol Chem 267: 25889–25897. 20. Yanagisawa H, Komuta Y, Kawano H, Toyoda M, Sango K (2010) Pleiotrophin induces neurite outgrowth and up-regulates growth-associated protein (GAP)-43 mRNA through the ALK/GSK3beta/beta-catenin signaling in developing mouse neurons. Neurosci Res 66: 111–116. 21. Czubayko F, Schulte AM, Missner SC, Hsieh SS, Colley KJ, et al. (1995) Molecular and pharmacologic targeting of angiogenesis factors–the example of pleiotrophin. Breast Cancer Res Treat 36: 157–168. 22. Czubayko F, Schulte AM, Berchem GJ, Wellstein A (1996) Melanoma angiogenesis and metastasis modulated by ribozyme targeting of the secreted growth factor pleiotrophin. Proc Natl Acad Sci USA 93: 14753–14758. 23. Mi R, Chen W, Hoke A (2007) Pleiotrophin is a neurotrophic factor for spinal motor neurons. Proc Natl Acad Sci U S A 104: 4664–4669. 24. Souttou B, Ahmad S, Riegel AT, Wellstein A (1997) Signal transduction pathways involved in the mitogenic activity of pleiotrophin. Implication of mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. J Biol Chem 272: 19588–19593. 25. Bowden ET, Stoica GE, Wellstein A (2002) Anti-apoptotic signaling of pleiotrophin through its receptor, anaplastic lymphoma kinase. J Biol Chem 277: 35862–35868. 26. Zhang N, Zhong R, Wang ZY, Deuel TF (1997) Human breast cancer growth inhibited in vivo by a dominant negative pleiotrophin mutant. J Biol Chem 272: 16733–16736. 27. Weber D, Klomp HJ, Czubayko F, Wellstein A, Juhl H (2000) Pleiotrophin can be rate-limiting for pancreatic cancer cell growth. Cancer Research 60: 5284– 5288. 28. Czubayko F, Downing SG, Hsieh SS, Goldstein DJ, Lu PY, et al. (1997) Adenovirus-mediated transduction of ribozymes abrogates HER-2/neu and pleiotrophin expression and inhibits tumor cell proliferation. Gene Ther 4: 943– 949. 29. Jung C-G, Hida H, Nakahira K, Ikenaka K, Kim H-J, et al. (2004) Pleiotrophin mRNA is highly expressed in neural stem (progenitor) cells of mouse ventral mesencephalon and the product promotes production of dopaminergic neurons from embryonic stem cell-derived nestin-positive cells. FASEB J 18: 1237–1239. 30. Yang X, Tare RS, Partridge KA, Roach HI, Clarke NMP, et al. (2003) Induction of human osteoprogenitor chemotaxis, proliferation, differentiation, and bone formation by osteoblast stimulating factor-1/pleiotrophin: osteocon- ductive biomimetic scaffolds for tissue engineering. J Bone Miner Res 18: 47–57. 31. Himburg HA, Muramoto GG, Daher P, Meadows SK, Russell JL, et al. (2010) Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nat Med 16: 475–482. 32. Wellstein A, Fang WJ, Khatri A, Lu Y, Swain SS, et al. (1992) A heparin- binding growth factor secreted from breast cancer cells homologous to a developmentally regulated cytokine. J Biol Chem 267: 2582–2587. 33. Chauhan AK, Li YS, Deuel TF (1993) Pleiotrophin transforms NIH 3T3 cells and induces tumors in nude mice. Proc Natl Acad Sci USA 90: 679–682. 34. Schulte AM, Lai S, Kurtz A, Czubayko F, Riegel AT, et al. (1996) Human trophoblast and choriocarcinoma expression of the growth factor pleiotrophin attributable to germ-line insertion of an endogenous retrovirus. Proc Natl Acad Sci USA 93: 14759–14764. 35. Czubayko F, Riegel AT, Wellstein A (1994) Ribozyme-targeting elucidates a direct role of pleiotrophin in tumor growth. J Biol Chem 269: 21358–21363. 36. Chang Y, Zuka M, Perez-Pinera P, Astudillo A, Mortimer J, et al. (2007) Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment. Proc Natl Acad Sci U S A 104: 10888–10893. 37. Perez-Pinera P, Chang Y, Astudillo A, Mortimer J, Deuel TF (2007) Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer. Biochem Biophys Res Commun 358: 399–403. 38. Perez-Pinera P, Garcia-Suarez O, Menendez-Rodriguez P, Mortimer J, Chang Y, et al. (2007) The receptor protein tyrosine phosphatase (RPTP)beta/zeta is expressed in different subtypes of human breast cancer. Biochem Biophys Res Commun 362: 5–10. 39. Ledoux D, Caruelle D, Sabourin JC, Liu J, Crepin M, et al. (1997) Cellular distribution of the angiogenic factor heparin affin regulatory peptide (HARP) mRNA and protein in the human mammary gland. J Histochem Cytochem 45: 1239–1245. 40. Marzan CV, Kupumbati TS, Bertran SP, Samuels T, Leibovitch B, et al. (2011) Adipocyte derived paracrine mediators of mammary ductal morphogenesis controlled by retinoic acid receptors. Dev Biol 349: 125–136. 41. Kouros-Mehr H, Werb Z (2006) Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn 235: 3404–3412. 42. D’Cruz CM, Moody SE, Master SR, Hartman JL, Keiper EA, et al. (2002) Persistent parity-induced changes in growth factors, TGF-beta3, and differen- tiation in the rodent mammary gland. Mol Endocrinol 16: 2034–2051. 43. Rosner B, Colditz GA, Willett WC (1994) Reproductive risk factors in a prospective study of breast cancer: the Nurses’ Health Study. Am J Epidemiol 139: 819–835. PTN in the Mammary Gland 44. MacMahon B, Cole P, Lin TM, Lowe CR, Mirra AP, et al. (1970) Age at first birth and breast cancer risk. Bull World Health Organ 43: 209–221. 45. Thordarson G, Jin E, Guzman RC, Swanson SM, Nandi S, et al. (1995) Refractoriness to mammary tumorigenesis in parous rats: is it caused by persistent changes in the hormonal environment or permanent biochemical alterations in the mammary epithelia? Carcinogenesis 16: 2847–2853. 46. Yang J, Yoshizawa K, Nandi S, Tsubura A (1999) Protective effects of pregnancy and lactation against N-methyl-N-nitrosourea-induced mammary carcinomas in female Lewis rats. Carcinogenesis 20: 623–628. 47. Russo J, Tay LK, Russo IH (1982) Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res Treat 2: 5–73. 48. Garland HO, Atherton JC, Baylis C, Morgan MR, Milne CM (1987) Hormone profiles for progesterone, oestradiol, prolactin, plasma renin activity, aldosterone and corticosterone during pregnancy and pseudopregnancy in two strains of rat: correlation with renal studies. J Endocrinol 113: 435–444. 49. Debnath J, Muthuswamy SK, Brugge JS (2003) Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30: 256–268. 50. Debnath J, Brugge JS (2005) Modelling glandular epithelial cancers in three- dimensional cultures. Nat Rev Cancer 5: 675–688. 51. O’Brien J, Fornetti J, Schedin P (2010) Isolation of mammary-specific extracellular matrix to assess acute cell-ECM interactions in 3D culture. J Mammary Gland Biol Neoplasia 15: 353–364. 52. O’Brien LE, Zegers MM, Mostov KE (2002) Opinion: Building epithelial architecture: insights from three-dimensional culture models. Nat Rev Mol Cell Biol 3: 531–537. 53. O’Brien LE, Jou TS, Pollack AL, Zhang Q, Hansen SH, et al. (2001) Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nat Cell Biol 3: 831–838. 54. Russo IHRaJ (1978) Developmental Stage of the Rat Mammary Gland as Determinant of Its Susceptibility to 7,12-Dimethylbenz[a]anthracene. J NATL Cancer Insitute 61: 1439–1450. 55. LaRocca J, Pietruska J, Hixon M (2011) Akt1 is essential for postnatal mammary gland development, function, and the expression of Btn1a1. PLoS One 6: e24432. 56. Hennighausen L, Robinson GW (2005) Information networks in the mammary gland. Nat Rev Mol Cell Biol 6: 715–725. 57. Ball SM (1998) The development of the terminal end bud in the prepubertal- pubertal mouse mammary gland. Anat Rec 250: 459–464. 58. Whyte J, Bergin O, Bianchi A, McNally S, Martin F (2009) Key signalling nodes in mammary gland development and cancer. Mitogen-activated protein kinase signalling in experimental models of breast cancer progression and in mammary gland development. Breast Cancer Res 11: 209. 59. Cicalese A, Bonizzi G, Pasi CE, Faretta M, Ronzoni S, et al. (2009) The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138: 1083–1095. 60. Tiede BJ, Owens LA, Li F, Decoste C, Kang Y (2009) A Novel Mouse Model for Non-Invasive Single Marker Tracking of Mammary Stem Cells In Vivo Reveals Stem Cell Dynamics throughout Pregnancy. PLoS ONE 4: e8035. 61. Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, et al. (2006) Generation of a functional mammary gland from a single stem cell. Nature 439: 84–88. 62. Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, et al. (2006) Purification and unique properties of mammary epithelial stem cells. Nature: 1–5. 63. Liao M-J, Zhang CC, Zhou B, Zimonjic DB, Mani SA, et al. (2007) Enrichment of a Population of Mammary Gland Cells that Form Mammospheres and Have In vivo Repopulating Activity. Cancer Research 67: 8131–8138. 64. Welm BE, Tepera SB, Venezia T, Graubert TA, Rosen JM, et al. (2002) Sca- 1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol 245: 42–56. 65. Bachelard-Cascales E, Chapellier M, Delay E, Pochon G, Voeltzel T, et al. (2010) The CD10 Enzyme Is a Key Player to Identify and Regulate Human Mammary Stem Cells. STEM CELLS 28: 1081–1088. 66. Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, et al. (2003) In vitro propagation and transcriptional profiling of human mammary stem/ progenitor cells. Genes Dev 17: 1253–1270. 67. Visvader JE, Lindeman GJ (2006) Mammary stem cells and mammopoiesis. Cancer Res 66: 9798–9801. 68. Hienola A, Pekkanen M, Raulo E, Vanttola P, Rauvala H (2004) HB-GAM inhibits proliferation and enhances differentiation of neural stem cells. Mol Cell Neurosci 26: 75–88. 69. Kadomatsu K, Tomomura M, Muramatsu T (1988) cDNA cloning and sequencing of a new gene intensely expressed in early differentiation stages of embryonal carcinoma cells and in mid-gestation period of mouse embryogenesis. Biochem Biophys Res Commun 151: 1312–1318. 70. Stoica GE, Kuo A, Powers C, Bowden E, Sale EB, et al. (2002) Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. J Biol Chem 277: 35990–35998. 71. Kuo AH, Stoica GE, Riegel AT, Wellstein A (2007) Recruitment of insulin receptor substrate-1 and activation of NF-kappaB essential for midkine growth signaling through anaplastic lymphoma kinase. Oncogene 26: 859–869. 72. Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, et al. (2001) Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. J Biol Chem 276: 16772–16779. PLOS ONE | www.plosone.org 13 October 2012 | Volume 7 | Issue 10 | e47876