Skip to main content

Advertisement

SpringerLink
Log in

Transgenic Models to Study Actions of Prolactin in Mammary Neoplasia

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Transgenic models to explore the role of prolactin and its interactions with other factors in mammary oncogenesis have begun to reveal the dynamic contributions of prolactin to the development and progression of this disease. Targeting prolactin to mammary epithelial cells mimics the local production of this hormone that is prominent in women, and permits studies in the absence of effects on the ovarian steroid milieu. These models have demonstrated that local production of prolactin is sufficient to induce mammary tumors after a long latency. Prolactin also can potentiate actions of other oncogenic stimuli, decreasing tumor latency and increasing incidence in several models. Augmented proliferation, without alteration of apoptosis, is a consistent feature. Pathways in addition to the well-characterized Jak2-Stat5 pathway, including ERK1/2 and Akt1/2, are implicated in these actions. These studies have also revealed a complex relationship with estrogen; while prolactin increases ERα expression, it does not require estrogenic ligand for lesion development, and indeed, in combination with the EGFR ligand, TGFα, prolactin can contribute to estrogen insensitivity. These studies highlight the utility of these models to decipher the interplay between prolactin and other oncogenic factors in breast cancer, with implications for preventative and therapeutic strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1

Similar content being viewed by others

Abbreviations

APC:

adenomatous polyposis coli

βLG:

β-lactoglobulin

caPRLR:

constitutively active prolactin receptor

DMBA:

9,10-dimethyl-1,2-benzanthracene

DCIS:

ductal carcinoma in situ

ENU:

N-ethyl-N-nitrosourea

ER:

estrogen receptor

GH:

growth hormone

hPAP:

human placental alkaline phosphatase

MECs:

mammary epithelial cells

MT:

metallothionein

MMTV:

mouse mammary tumor virus

NRL:

neu-related lipocalin

PRL:

prolactin

PRLR:

prolactin receptor

TGFα:

transforming growth factor alpha

WAP:

whey acidic protein

References

  1. Welsch CW, Nagasawa H. Prolactin and murine mammary tumorigenesis: a review. Cancer Res. 1977;37:951–63.

    PubMed  CAS  Google Scholar 

  2. Welsch CW. Prolactin and the development and progression of early neoplastic mammary gland lesions. Cancer Res. 1978;38:4054–8.

    PubMed  CAS  Google Scholar 

  3. Bern HA, Nandi S. Recent studies of the hormonal influence in mouse mammary tumorigenesis. Prog in Exp Tumor Res. 1961;2:90–144.

    CAS  Google Scholar 

  4. Imagawa W, Bandyopadhyay GK, Nandi S. Regulation of mammary epithelial cell growth in mice and rats. Endocrine Rev. 1990;11:494–523.

    CAS  Google Scholar 

  5. Welsch CW, Gribler C. Prophylaxis of spontaneously developing mammary carcinoma in C3H- HeJ female mice by suppression of prolactin. Cancer Res. 1973;33:2939–46.

    PubMed  CAS  Google Scholar 

  6. Welsch CW, Brown CK, Goodrich-Smith M, Chiusano J, Moon RC. Synergistic effect of chronic prolactin suppression and retinoid treatment in the prophylaxis of N-methyl-N-nitrosourea-induced mammary tumorigenesis in female Sprague–Dawley rats. Cancer Res. 1980;40:3095–8.

    PubMed  CAS  Google Scholar 

  7. Welsch CW, Brown CK, Goodrich-Smith M, Van J, Denenberg B, Anderson TM, et al. Inhibition of mammary tumorigenesis in carcinogen-treated Lewis rats by suppression of prolactin secretion. J Natl Cancer Inst. 1979;63:1121–4.

    PubMed  CAS  Google Scholar 

  8. Welsch CW, Goodrich-Smith M, Brown CK, Roth L. The prophylaxis of rat and mouse mammary gland tumorigenesis by suppression of prolactin secretion: a reappraisal. Breast Cancer Res Treat. 1981;1:225–32.

    PubMed  CAS  Google Scholar 

  9. Huseby RA, Soares MJ, Talamantes F. Ectopic pituitary grafts in mice: hormone levels, effects on fertility, and the development of adenomyosis uteri, prolactinomas, and mammary carcinomas. Endocrinology. 1985;116:1440–8.

    PubMed  CAS  Google Scholar 

  10. Medina D, Kittrell FS, Shepard A, Contreras A, Rosen JM, Lydon J. Hormone dependence in premalignant mammary progression. Cancer Res. 2003;63:1067–72.

    PubMed  CAS  Google Scholar 

  11. Snyderwine EG. Mammary gland carcinogenesis by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in rats: possible mechanisms. Cancer Lett. 1999;143:211–5.

    PubMed  CAS  Google Scholar 

  12. Cardiff RD, Anver MR, Gusterson BA, Hennighausen L, Jensen RA, Merino MJ, et al. The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting. Oncogene. 2000;19:968–88.

    PubMed  CAS  Google Scholar 

  13. Green JE, Hudson T. The promise of genetically engineered mice for cancer prevention studies. Nat Rev Cancer. 2005;5:184–98.

    PubMed  CAS  Google Scholar 

  14. Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, et al. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. 2007;8:R76.

    PubMed  Google Scholar 

  15. Green JE. A cross-species systems biology approach to mammary cancer: what can the mouse teach us about human cancer? AACR Conference Proceedings. 2005.

  16. Clevenger CV, Furth PA, Hankinson SE, Schuler LA. Role of prolactin in mammary carcinoma. Endocr Rev. 2003;24:1–27.

    PubMed  CAS  Google Scholar 

  17. Goffin V, Bernichtein S, Touraine P, Kelly PA. Development and potential clinical uses of human prolactin receptor antagonists. Endocr Rev. 2005;26:400–22.

    PubMed  CAS  Google Scholar 

  18. Ben-Jonathan N, Mershon JL, Allen DL, Steinmetz RW. Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocr Rev. 1996;17:639–69.

    PubMed  CAS  Google Scholar 

  19. Schroeder MD, Rose-Hellekant T, Sandgren EP, Schuler LA. Dysregulation of signal transducers and activators of transcription 1, 3, and 5 and prolactin receptors by overexpression of mammary TGFα. Mol Cell Endocrinol. 2001;175:173–83.

    PubMed  CAS  Google Scholar 

  20. Manhes C, Kayser C, Bertheau P, Kelder B, Kopchick JJ, Kelly PA, et al. Local over-expression of prolactin in differentiating mouse mammary gland induces functional defects and benign lesions, but no carcinoma. J Endocrinol. 2006;190:271–85.

    PubMed  CAS  Google Scholar 

  21. Stocco C, Telleria C, Gibori G. The molecular control of corpus luteum formation, function, and regression. Endocr Rev. 2007;28:117–49.

    PubMed  CAS  Google Scholar 

  22. Sorlie T. Molecular portraits of breast cancer: tumour subtypes as distinct disease entities. Eur J Cancer [A]. 2004;40:2667–75.

    CAS  Google Scholar 

  23. Smeds J, Miller LD, Bjohle J, Hall P, Klaar S, Liu ET, et al. Gene profile and response to treatment. Ann Oncol. 2005;16(Suppl 2):ii195–202.

    PubMed  Google Scholar 

  24. Oh DS, Troester MA, Usary J, Hu Z, He X, Fan C, et al. Estrogen-regulated genes predict survival in hormone receptor-positive breast cancers. J Clin Oncol. 2006;24:1656–64.

    PubMed  CAS  Google Scholar 

  25. Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, et al. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics. 2006;7:96.

    PubMed  Google Scholar 

  26. Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, et al. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst. 2006;98:262–72.

    Article  PubMed  CAS  Google Scholar 

  27. Sims AH, Howell A, Howell SJ, Clarke RB. Origins of breast cancer subtypes and therapeutic implications. Nat Clin Pract Oncol. 2007;4:516–25.

    PubMed  CAS  Google Scholar 

  28. Palmer CA, Neville MC, Anderson SM, McManaman JL. Analysis of lactation defects in transgenic mice. J Mammary Gland Biol Neoplasia. 2006;11:269–82.

    PubMed  Google Scholar 

  29. Yarus S, Hadsell D, Rosen JM. Engineering transgenes for use in the mammary gland. Genet Eng. 1996;18:57–81.

    CAS  Google Scholar 

  30. Hennighausen L. Transgenic models to study mammary development, function and cancer. http://mammary nih gov/models/transgenics/index html. 2000.

  31. Sandgren EP, Schroeder JA, Qui TH, Palmiter RD, Brinster RL, Lee DC. Inhibition of mammary gland involution is associated with TGFα but not c-myc-induced tumorigenesis in transgenic mice. Cancer Res. 1995;55:3915–27.

    PubMed  CAS  Google Scholar 

  32. Otten AD, Sanders MM, McKnight GS. The MMTV LTR promoter is induced by progesterone and dihydrotestosterone but not by estrogen. Mol Endocrinol. 1988;2:143–7.

    PubMed  CAS  Google Scholar 

  33. Qin W, Golovkina TV, Peng T, Nepomnaschy I, Buggiano V, Piazzon I, Ross SR. Mammary gland expression of mouse mammary tumor virus is regulated by a novel element in the long terminal repeat. J Virol. 1999;73:368–76.

    PubMed  CAS  Google Scholar 

  34. Stoesz SP, Gould MN. Overexpression of neu-related lipocalin (NRL) in neu-initiated but not ras or chemically initiated rat mammary carcinomas. Oncogene. 1995;11:2233–41.

    PubMed  CAS  Google Scholar 

  35. Rose-Hellekant TA, Arendt LM, Schroeder MD, Gilchrist K, Sandgren EP, Schuler LA. Prolactin induces ERα-positive and ERα-negative mammary cancer in transgenic mice. Oncogene. 2003;22:4664–74.

    PubMed  CAS  Google Scholar 

  36. Rose-Hellekant TA, Schroeder MD, Brockman JL, Zhdankin O, Bolstad R, Chen KS, et al. Estrogen receptor positive mammary tumorigenesis in TGFα transgenic mice progresses with progesterone receptor loss. Oncogene. 2007;26:5238–46.

    PubMed  CAS  Google Scholar 

  37. Arendt LM, Schuler LA. Prolactin drives ERα-dependent ductal expansion and synergizes with TGFa to induce mammary tumors in males. Am J Pathol. 2008;172:194–202.

    Google Scholar 

  38. Bchini O, Andres A-C, Schubaur B, Mehtali M, LeMeur M, Lathe R, Gerlinger P. Precocious mammary gland development and milk protein synthesis in transgenic mice ubiquitously expressing human growth hormone. Endocrinology. 1991;128:539–46.

    PubMed  CAS  Google Scholar 

  39. Tornell J, Carlsson B, Pohjanen P, Wennbo H, Rymo L, Isaksson O. High frequency of mammary adenocarcinomas in metallothionein promotor-human growth hormone transgenic mice created from two different strains of mice. J Steroid Biochem Mol Biol. 1992;43:237–42.

    PubMed  CAS  Google Scholar 

  40. Tornell J, Rymo L, Isaksson OG. Induction of mammary adenocarcinomas in metallothionein promoter-human growth hormone transgenic mice. Int J Cancer. 1991;49:114–7.

    PubMed  CAS  Google Scholar 

  41. Wennbo H, Gebre-Medhin M, Gritli-Linde A, Ohlsson C, Isaksson OGP, Törnell J. Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice. J Clin Invest. 1997;100:2744–51.

    Article  PubMed  CAS  Google Scholar 

  42. Tomblyn S, Langenheim JF, Scotti M, Chen WY. Microarray analysis of the gene alternations in the mammary gland of the prolactin/neu bi-transgenic mice that are resistant to neu-induced mammary tumors. 89th Annual Meeting of the Endocrine Society, Toronto. 2007. p. 2–385.

  43. Frasor J, Gibori G. Prolactin regulation of estrogen receptor expression. Trends Endocrinol Metab. 2003;14:118–23.

    PubMed  CAS  Google Scholar 

  44. Naylor MJ, Lockefeer JA, Horseman ND, Ormandy CJ. Prolactin regulates mammary epithelial cell proliferation via autocrine/paracrine mechanism. Endocrine. 2003;20:111–4.

    PubMed  CAS  Google Scholar 

  45. Gourdou I, Paly J, Hue-Beauvais C, Pessemesse L, Clark J, Djiane J. Expression by transgenesis of a constitutively active mutant form of the prolactin receptor induces premature abnormal development of the mouse mammary gland and lactation failure. Biol Reprod. 2004;70:718–28.

    PubMed  CAS  Google Scholar 

  46. Brisken C, Kaur S, Chavarria TE, Binart N, Sutherland RL, Weinberg RA, et al. Prolactin controls mammary gland development via direct and indirect mechanisms. Dev Biol. 1999;210:96–106.

    PubMed  CAS  Google Scholar 

  47. Vomachka AJ, Pratt SL, Lockefeer JA, Horseman ND. Prolactin gene-disruption arrests mammary gland development and retards T-antigen-induced tumor growth. Oncogene. 2000;19:1077–84.

    PubMed  CAS  Google Scholar 

  48. Oakes SR, Robertson FG, Kench JG, Gardiner-Garden M, Wand MP, Green JE, et al. Loss of mammary epithelial prolactin receptor delays tumor formation by reducing cell proliferation in low-grade preinvasive lesions. Oncogene. 2007;26:543–53.

    PubMed  CAS  Google Scholar 

  49. Stern DF. ErbBs in mammary development. Exp Cell Res. 2003;284:89–98.

    PubMed  CAS  Google Scholar 

  50. Snedeker SM, Brown CF, DiAugustine RP. Expression and functional properties of TGFα and EGF during mouse mammary gland ductal morphogenesis. Proc Natl Acad Sci USA. 1991;88:276–80.

    PubMed  CAS  Google Scholar 

  51. Troyer KL, Lee DC. Regulation of mouse mammary gland development and tumorigenesis by the ERBB signaling network. J Mammary Gland Biol Neoplasia. 2001;6:7–21.

    PubMed  CAS  Google Scholar 

  52. Yarden Y. The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities. Eur J Cancer [A]. 2001;37:S3–8.

    CAS  Google Scholar 

  53. Holbro T, Civenni G, Hynes NE. The ErbB receptors and their role in cancer progression. Exp Cell Res. 2003;284:99–110.

    PubMed  CAS  Google Scholar 

  54. Abd El-Rehim DM, Pinder SE, Paish CE, Bell JA, Rampaul RS, Blamey RW, et al. Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma. Br J Cancer. 2004;91:1532–42.

    PubMed  CAS  Google Scholar 

  55. Chrysogelos SA, Dickson RB. EGF receptor expression, regulation, and function in breast cancer. Br Can Res Treat. 1994;29:29–40.

    CAS  Google Scholar 

  56. Pilichowska M, Kimura N, Fujiwara H, Nagura H. Immunohistochemical study of TGFα, TGFβ1, EGFR, and IGF-1 expression in human breast carcinoma. Mod Pathol. 1997;10:969–75.

    PubMed  CAS  Google Scholar 

  57. Panico L, D’Antonio A, Salvatore G, Mezza E, Tortora G, De Laurentiis M, et al. Differential immunohistochemical detection of TGFα, amphiregulin and CRIPTO in human normal and malignant breast tissues. Int J Cancer. 1996;65:51–6.

    PubMed  CAS  Google Scholar 

  58. Nicholson RI, McClelland RA, Gee JMW, Manning DL, Cannon P, Robertson JFR, et al. TGFα and endocrine sensitivity in breast cancer. Cancer Res. 1994;54:1684–9.

    PubMed  CAS  Google Scholar 

  59. Bates SE, Davidson NE, Valverius EM, Freter CE, Dickson RB, Tam JP, et al. Expression of TGFα and its messenger ribonucleic acid in human breast cancer: its regulation by estrogen and its possible functional significance. Mol Endocrinol. 1988;2:543–55.

    PubMed  CAS  Google Scholar 

  60. Auvinen PK, Lipponen PK, Kataja VV, Johansson RT, Syrjanen KJ. Prognostic significance of TGFα expression in breast cancer. Acta Oncol. 1996;35:995–8.

    PubMed  CAS  Google Scholar 

  61. Waterman H, Sabanai I, Geiger B, Yarden Y. Alternative intracellular routing of ErbB receptors may determine signaling potency. J Biol Chem. 1998;273:13819–27.

    PubMed  CAS  Google Scholar 

  62. Normanno N, Bianco C, De Luca A, Salomon DS. The role of EGF-related peptides in tumor growth. Front Biosci. 2001;6:D685–707.

    PubMed  CAS  Google Scholar 

  63. Valabrega G, Montemurro F, Sarotto I, Petrelli A, Rubini P, Tacchetti C, et al. TGFα expression impairs Trastuzumab-induced HER2 downregulation. Oncogene. 2005;24:3002–10.

    PubMed  CAS  Google Scholar 

  64. Smith GH, Sharp R, Kordon EC, Jhappan C, Merlino G. TGFα promotes mammary tumorigenesis through selective survival and growth of secretory epithelial cells. Am J Pathol. 1995;147:1081–96.

    PubMed  CAS  Google Scholar 

  65. Matsui Y, Halter SAHJT, Hogan BLM, Coffey RJ. Development of mammary hyperplasia and neoplasia in MMTV-TGFα transgenic mice. Cell. 1990;61:1147–55.

    PubMed  CAS  Google Scholar 

  66. Rose-Hellekant TA, Gilchrist K, Sandgren EP. Strain background alters mammary gland lesion phenotype in TGFα transgenic mice. Am J Pathol. 2002;161:1439–47.

    PubMed  CAS  Google Scholar 

  67. Jhappan C, Stahle C, Harkins RN, Fausto N, Smith GH, Merlino GT. TGF-α overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell. 1990;61:1137–46.

    PubMed  CAS  Google Scholar 

  68. Humphreys RC, Hennighausen L. Transforming growth factor alpha and mouse models of human breast cancer. Oncogene. 2000;19:1085–91.

    PubMed  CAS  Google Scholar 

  69. Quijano VJ Jr., Sheffield LG. Prolactin decreases epidermal growth factor receptor kinase activity via a phosphorylation-dependent mechanism. J Biol Chem. 1998;273:1200–7.

    PubMed  CAS  Google Scholar 

  70. Johnson JL, Fenton SE, Sheffield LG. Prolactin inhibits epidermal growth factor-induced ras-MAPK signaling in mammary epithelial cells. J Biol Chem. 1996;271:21574–8.

    PubMed  CAS  Google Scholar 

  71. Humphreys RC, Hennighausen L. Signal transducer and activator of transcription 5a influences mammary epithelial cell survival and tumorigenesis. Cell Growth Differ. 1999;10:685–94.

    PubMed  CAS  Google Scholar 

  72. Hennighausen L, Robinson GW. Signaling pathways in mammary gland development. Dev Cell. 2001;1:467–75.

    PubMed  CAS  Google Scholar 

  73. Arendt LM, Rose-Hellekant TA, Sandgren EP, Schuler LA. Prolactin potentiates TGFα induction of mammary neoplasia in transgenic mice. Am J Pathol. 2006;168:1365–74.

    PubMed  CAS  Google Scholar 

  74. Wiesen JF, Young P, Werb Z, Cunha GR. Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development. Development. 1999;2:335–44.

    Google Scholar 

  75. Hovey RC, Trott JF, Ginsburg E, Goldhar A, Sasaki MM, Fountain SJ, et al. Transcriptional and spatiotemporal regulation of prolactin receptor mRNA and cooperativity with progesterone receptor function during ductal branch growth in the mammary gland. Dev Dyn. 2001;222:192–205.

    PubMed  CAS  Google Scholar 

  76. Camarillo IG, Thordarson G, Moffat JG, Van Horn KM, Binart N, Kelly PA, et al. Prolactin receptor expression in the epithelia and stroma of the rat mammary gland. J Endocrinol. 2001;171:85–95.

    PubMed  CAS  Google Scholar 

  77. Roovers K, Assoian RK. Integrating the MAP kinase signal into the G1 phase cell cycle machinery. BioEssays. 2000;22:818–26.

    PubMed  CAS  Google Scholar 

  78. Lenferink AE, Simpson JF, Shawver LK, Coffey RJ, Forbes JT, Arteaga CL. Blockade of the epidermal growth factor receptor tyrosine kinase suppresses tumorigenesis in MMTV/Neu + MMTV/TGFα bigenic mice. Proc Natl Acad Sci USA. 2000;97:9609–14.

    PubMed  CAS  Google Scholar 

  79. Gutzman JH, Nikolai SE, Rugowski DE, Watters JJ, Schuler LA. Prolactin and estrogen enhance the activity of Activating Protein-1 in breast cancer cells: role of ERK1/2-mediated signals to c-fos. Mol Endocrinol. 2005;19:1765–78.

    PubMed  CAS  Google Scholar 

  80. Huang Y, Li X, Jiang J, Frank SJ. Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells. Oncogene. 2006;25:7565–76.

    PubMed  CAS  Google Scholar 

  81. Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J. Molecular interpretation of ERK signal duration by immediate early gene products. Nat Cell Biol. 2002;4:556–64.

    PubMed  CAS  Google Scholar 

  82. Kirkegaard T, Witton CJ, McGlynn LM, Tovey SM, Dunne B, Lyon A, Bartlett JM. AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol. 2005;207:139–46.

    PubMed  CAS  Google Scholar 

  83. Tokunaga E, Kataoka A, Kimura Y, Oki E, Mashino K, Nishida K, et al. The association between Akt activation and resistance to hormone therapy in metastatic breast cancer. Eur J Cancer. 2006;42:629–35.

    PubMed  CAS  Google Scholar 

  84. Clark AS, West K, Streicher S, Dennis PA. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther. 2002;1:707–17.

    PubMed  CAS  Google Scholar 

  85. Ursini-Siegel J, Schade B, Cardiff RD, Muller WJ. Insights from transgenic mouse models of ERBB2-induced breast cancer. Nat Rev Cancer. 2007;7:389–97.

    PubMed  CAS  Google Scholar 

  86. Tomblyn S, Springs AEB, Langenheim JF, Chen WY. A multifaceted, targeted combination therapy using three novel prolactin receptor antagonist based fusion proteins which significantly inhibits tumor recurrence in HER2/neu mice. 89th Annual Meeting of the Endocrine Society, Toronto. 2007; OR43–1.

  87. Sarkisian CJ, Keister BA, Stairs DB, Boxer RB, Moody SE, Chodosh LA. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat Cell Biol. 2007;9:493–505.

    PubMed  CAS  Google Scholar 

  88. Andrechek ER, Hardy WR, Laing MA, Muller WJ. Germ-line expression of an oncogenic erbB2 allele confers resistance to erbB2-induced mammary tumorigenesis. Proc Natl Acad Sci USA. 2004;101:4984–9.

    PubMed  CAS  Google Scholar 

  89. Park BW, Kim KS, Heo MK, Ko SS, Hong SW, Yang WI, et al. Expression of ERβ in normal mammary and tumor tissues: is it protective in breast carcinogenesis? Br Cancer Res Treat. 2003;80:79–85.

    CAS  Google Scholar 

  90. Shaaban AM, O’Neill PA, Davies MPA, Sibson R, West CR, Smith PH, Foster CS. Declining ERβ expression defines malignant progression of human breast neoplasia. Am J Surg Pathol. 2003;27:1502–12.

    PubMed  Google Scholar 

  91. Paruthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, Leitman DC. Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res. 2004;64:423–8.

    PubMed  CAS  Google Scholar 

  92. Brown P, Fuqua S, Allred C. Pathogenesis of estrogen-receptor-positive and -negative breast cancer. In: Ethier SP, editor. Contemporary endocrinology: endocrine oncology. Totowa (NJ): Humana Press Inc; 2000. p. 49–68.

    Google Scholar 

  93. Nicholson RI, Gee JMW. Oestrogen and growth factor cross-talk and endocrine insensitivity and acquired resistance in breast cancer. Br J Cancer. 2000;82:501–13.

    PubMed  CAS  Google Scholar 

  94. Normanno N, Di Maio M, De Maio E, De Luca A, de Matteis A, Giordano A, et al. Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer. Endocr Relat Cancer. 2005;12:721–47.

    PubMed  CAS  Google Scholar 

  95. Tworoger SS, Eliassen AH, Sluss P, Hankinson SE. A prospective study of plasma prolactin concentrations and risk of premenopausal and postmenopausal breast cancer. J Clin Oncol. 2007;25:1482–8.

    PubMed  CAS  Google Scholar 

  96. Tworoger SS, Hankinson SE. Prolactin and breast cancer risk. Cancer Lett. 2006;243:160–9.

    PubMed  CAS  Google Scholar 

  97. Gutzman JH, Miller KK, Schuler LA. Endogenous hPRL and not exogenous hPRL induces ERα and PRLR expression and increases estrogen responsiveness in breast cancer cells. J Steroid Biochem Mol Biol. 2004;88:69–77.

    PubMed  CAS  Google Scholar 

  98. Ormandy CJ, Hall RE, Manning DL, Robertson JFR, Blamey RW, Kelly PA, et al. Coexpression and cross-regulation of the prolactin receptor and sex steroid hormone receptors in breast cancer. J Clin Endocrinol Metab. 1997;82:3692–9.

    PubMed  CAS  Google Scholar 

  99. Murphy LJ, Murphy LC, Vrhovsek E, Sutherland RL, Lazarus L. Correlation of lactogenic receptor concentration in human breast cancer with estrogen receptor concentration. Cancer Res. 1984;44:1963–8.

    PubMed  CAS  Google Scholar 

  100. Bonnetere J, Peyrat JP, Beuscart R, Demaille A. Biological and clinical aspects of prolactin receptor (PRL- R) in human breat cancer. J Sterioid Biochem Mol Biol. 1990;37:977–81.

    Google Scholar 

  101. Reynolds C, Montone KT, Powell CM, Tomaszewski JE, Clevenger CV. Expression of prolactin and its receptor in human breast carcinoma. Endocrinology. 1997;138:5555–60.

    PubMed  CAS  Google Scholar 

  102. Gill S, Peston D, Vonderhaar BK, Shousha S. Expression of prolactin receptors in normal, benign, and malignant breast tissue: an immunohistological study. J Clin Pathol. 2001;54:956–60.

    PubMed  CAS  Google Scholar 

  103. Ben David M, Wittliff JL, Fekete M, Kadar T, Biran S, Schally AV. Lack of relationship between the levels of prolactin receptors and steroid receptors in women with breast cancer. Biomed Pharmacother. 1988;42:327–34.

    PubMed  CAS  Google Scholar 

  104. De Placido S, Gallo C, Perrone F, Marinelli A, Pagliarulo C, Carlomagno C, et al. Prolactin receptor does not correlate with oestrogen and progesterone receptors in primary breast cancer and lacks prognostic significance Ten year results of the Naples adjuvant (GUN) study. Br J Cancer. 1990;62:643–6.

    PubMed  Google Scholar 

  105. Waseda N, Kato Y, Imura H, Kurata M. Prognostic value of estrogen and prolactin receptor analysis in human breast cancer. Jpn J Cancer Res. 1985;76:517–23.

    PubMed  CAS  Google Scholar 

  106. Grimm SL, Seagroves TN, Kabotyanski EB, Hovey RC, Vonderhaar BK, Lydon JP, et al. Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development. Mol Endocrinol. 2002;16:2675–91.

    PubMed  CAS  Google Scholar 

  107. Rosen JM. Hormone receptor patterning plays a critical role in normal lobuloalveolar development and breast cancer progression. Breast Dis. 2003;18:3–9.

    PubMed  CAS  Google Scholar 

  108. Chilton BS, Hewetson A. Prolactin and growth hormone signaling. Curr Top Dev Biol. 2005;68:1–23.

    PubMed  CAS  Google Scholar 

  109. Muldoon TG. Prolactin mediation of estrogen-induced changes in mammary tissue estrogen and progesterone receptors. Endocrinology. 1987;121:141–9.

    Article  PubMed  CAS  Google Scholar 

  110. Edery M, Imagawa W, Larson L, Nandi S. Regulation of estrogen and progesterone receptor levels in mouse mammary epithelial cells grown in serum-free collagen gel cultures. Endocrinology. 1985;116:105–12.

    Article  PubMed  CAS  Google Scholar 

  111. Cunha GR, Young P, Hom YK, Cooke PS, Taylor JA, Lubahn DB. Elucidation of a role for stromal steroid hormone receptors in mammary gland growth and development using tissue recombinants. J Mammary Gland Biol Neopl. 1997;2:393–402.

    CAS  Google Scholar 

  112. Mallepell S, Krust A, Chambon P, Brisken C. Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci USA. 2006;103:2196–201.

    PubMed  CAS  Google Scholar 

  113. Lannigan DA. Estrogen receptor phosphorylation. Steroids. 2003;68:1–9.

    PubMed  CAS  Google Scholar 

  114. Shupnik MA. Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Oncogene. 2004;23:7979–89.

    PubMed  CAS  Google Scholar 

  115. Coleman KM, Smith CL. Intracellular signaling pathways: nongenomic actions of estrogens and ligand-independent activation of estrogen receptors. Front Biosci. 2001;6:D1379–1391.

    PubMed  CAS  Google Scholar 

  116. Weigel NL, Moore NL. Steroid receptor phosphorylation: a key modulator of multiple receptor functions. Mol Endocrinol. 2007;21:2311–9.

    PubMed  CAS  Google Scholar 

  117. Land CE, Tokunaga M, Koyama K, Soda M, Preston DL, Nishimori I, Tokuoka S. Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950–1990. Radiat Res. 2003;160:707–17.

    PubMed  CAS  Google Scholar 

  118. Land CE. Studies of cancer and radiation dose among atomic bomb survivors. The example of breast cancer. JAMA. 1995;274:402–7.

    PubMed  CAS  Google Scholar 

  119. Chu EY, Hens J, Andl T, Kairo A, Yamaguchi TP, Brisken C, et al. Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development. 2004;131:4819–29.

    PubMed  CAS  Google Scholar 

  120. Cowin P, Rowlands TM, Hatsell SJ. Cadherins and catenins in breast cancer. Curr Opin Cell Biol. 2005;17:499–508.

    PubMed  CAS  Google Scholar 

  121. Liu BY, McDermott SP, Khwaja SS, Alexander CM. The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. Proc Natl Acad Sci USA. 2004;101:4158–63.

    PubMed  CAS  Google Scholar 

  122. Li Y, Welm B, Podsypanina K, Huang SX, Chamorro M, Zhang XM, et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci USA. 2003;100:15853–8.

    PubMed  CAS  Google Scholar 

  123. Farago M, Dominguez I, Landesman-Bollag E, Xu X, Rosner A, Cardiff RD, et al. Kinase-inactive glycogen synthase kinase 3beta promotes Wnt signaling and mammary tumorigenesis. Cancer Res. 2005;65:5792–801.

    PubMed  CAS  Google Scholar 

  124. Meniel V, Clarke AR. Wnt-cadherin connections in normal and neoplastic mammary epithelium. J Mammary Gland Biol Neoplasia. 2003;8:435–47.

    PubMed  Google Scholar 

  125. Méniel V, Hay T, Douglas-Jones A, Sansom OJ, Clarke AR. Mutations in Apc and p53 synergize to promote mammary neoplasia. Cancer Res. 2005;65:410–6.

    PubMed  Google Scholar 

  126. Brennan KR, Brown AM. Wnt proteins in mammary development and cancer. J Mammary Gland Biol Neoplasia. 2004;9:119–31.

    PubMed  Google Scholar 

  127. Kashiwaba M, Tamura G, Ishida M. Aberrations of the APC gene in primary breast carcinoma. J Cancer Res Clin Oncol. 1994;120:727–31.

    PubMed  CAS  Google Scholar 

  128. Medeiros AC, Nagai MA, Neto MM, Brentani RR. Loss of heterozygosity affecting the APC and MCC genetic loci in patients with primary breast carcinomas. Cancer Epidemiol Biomarkers Prev. 1994;3:331–3.

    PubMed  CAS  Google Scholar 

  129. Schlosshauer PW, Brown SA, Eisinger K, Yan Q, Guglielminetti ER, Parsons R, et al. APC truncation and increased beta-catenin levels in a human breast cancer cell line. Carcinogenesis. 2000;21:1453–6.

    PubMed  CAS  Google Scholar 

  130. Furuuchi K, Tada M, Yamada H, Kataoka A, Furuuchi N, Hamada J, et al. Somatic mutations of the APC gene in primary breast cancers. Am J Pathol. 2000;156:1997–2005.

    PubMed  CAS  Google Scholar 

  131. Dulaimi E, Hillinck J, Ibanez de Caceres I, Al Saleem T, Cairns P. Tumor suppressor gene promoter hypermethylation in serum of breast cancer patients. Clin Cancer Res. 2004;10:6189–93.

    PubMed  CAS  Google Scholar 

  132. Muller HM, Widschwendter A, Fiegl H, Ivarsson L, Goebel G, Perkmann E, et al. DNA methylation in serum of breast cancer patients: an independent prognostic marker. Cancer Res. 2003;63:7641–5.

    PubMed  Google Scholar 

  133. Moser AR, Mattes EM, Dove WF, Lindstrom MJ, Haag JD, Gould MN. Apc-min, a mutation in the murine Apc gene, predisposes to mammary carcinomas and focal alveolar hyperplasias. Proc Natl Acad Sci USA. 1993;90:8977–81.

    PubMed  CAS  Google Scholar 

  134. Tomblyn S, Langenheim JF, Jacquemart IC, Holle E, Chen WY. The role of human prolactin and its antagonist, G129R, in mammary gland development and DMBA-initiated tumorigenesis in transgenic mice. Int J Oncol. 2005;27:1381–9.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Drs. Kathleen O’Leary, Eric Sandgren and Serge Fuchs for helpful discussions. This study was supported in part by NIH K01 RR21858 (LMA) and R01 CA78312 (LAS).

Author information

Authors and Affiliations

  1. Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Dr., Madison, WI, 53706, USA

    Lisa M. Arendt & Linda A. Schuler

Authors
  1. Lisa M. Arendt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linda A. Schuler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Linda A. Schuler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arendt, L.M., Schuler, L.A. Transgenic Models to Study Actions of Prolactin in Mammary Neoplasia. J Mammary Gland Biol Neoplasia 13, 29–40 (2008). https://doi.org/10.1007/s10911-008-9073-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-008-9073-9

Keywords

Search

Navigation