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Prolactin as a Mitogen in Mammary Cells

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Abstract

Prolactin (PRL) acts as both a mitogen and a differentiating agent in the breast. The decision to respond to PRL as a mitogen by breast cells depends on the hormonal milieu in which the epithelial cell resides. In addition, PRL's action on the breast is regulated (1) at the level of the hormone itself; (2) at the receptor level; (3) at the level of selection of signaling pathway; and, (4) by combinations of these aspects. The development of cell lines containing only one class of the PRL receptors and showing qualitative differences in response and signaling pathways will help in understanding the pleiotropic nature of PRL action.

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REFERENCES

  1. B. K. Vonderhaar (1987). Prolactin: transport, function, and receptors in mammary gland development and differentiation. In M. C. Neville and C. W. Daniel (eds.), The Mammary Gland, Plenum Publishing Corp., New York, pp. 383–438.

    Google Scholar 

  2. Y. N. Sinha (1995). Structural variants of prolactin: Occurrence and physiological significance. Endocrine Reviews 16:354–369.

    Google Scholar 

  3. E. Ginsburg and B. K. Vonderhaar (1995). Prolactin synthesis and secretion by human breast cancer cells. Cancer Res. 55:2591–2595.

    Google Scholar 

  4. C. V. Clevenger and T. L. Plank (1997). Prolactin as an autocrine/paracrine factor in breast tissue. J. Mam. Gland Biol. Neoplasia 2(1):59–68.

    Google Scholar 

  5. B. K. Vonderhaar and R. Biswas (1987). Prolactin effects and regulation of its receptors in human mammary tumor cells. In D. Medina, W. Kidwell, G. Hepner, and E. Anderson (eds.), Cellular and Molecular Biology of Mammary Cancer, Plenum Publishing Corp., New York, pp. 205–219.

    Google Scholar 

  6. J. Mershon, W. Sall, N. Mitchner, and N. Ben-Jonathan (1995). Prolactin is a local growth factor in rat mammary tumors. Endocrinology 136:3619–3623.

    Google Scholar 

  7. C. Welsch and H. Nagasawa (1977). Prolactin and murine mammary tumorigenesis: a review. Cancer Res. 37:951–963.

    Google Scholar 

  8. W. Holtkamp, G. A. Nagel, H. E. Wander, H. F. Rauschecker, and D. VonHeyden (1984). Hyperprolactenemia is an indicator of progressive disease and poor prognosis in advanced breast cancer. Int. J. Cancer. 34:323–328.

    Google Scholar 

  9. H. Nagasawa, K. Miur, K. Niki, and H. Namiki (1985). Interrelationship between prolactin and progesterone in normal mammary gland growth in SHN virgin mice. Exp. Clin. Endocrinol. 86:357–360.

    Google Scholar 

  10. K. Plaut, M. Ikeda, and B. K. Vonderhaar (1993). Role of growth hormone and insulin-like growth factor 1 in mammary development. Endocrinology 133:1843–1848.

    Google Scholar 

  11. C. S. Atwood, M. Ikeda, and B. K. Vonderhaar (1995). Involution of mouse mammary glands in whole organ culture: a model for studying programmed cell death. Biochem. Biophys. Res. Commun. 207:860–867.

    Google Scholar 

  12. R. Banerjee and B. K. Vonderhaar (1992). Prolactin induced protein kinase C activity in a mouse mammary epithelial cell line NOG-8. Mol. Cell. Endocrinol. 90:61–67.

    Google Scholar 

  13. R. R. Love, D. R. Rose, T. S. Surawicz, and P. A. Newcomb (1991). Prolactin and growth hormone levels in premenopausal women with breast cancer and healthy women with a strong family history of breast cancer. Cancer 68:1401–1405.

    Google Scholar 

  14. W. B. Malarkey, M. Kennedy, L. E. Allred, and G. Milo (1983). Physiological concentrations of prolactin can promote the growth of human breast tumor cells in culture. J. Clin. Endocrinol. Metab. 56:673–677.

    Google Scholar 

  15. R. Biswas and B. K. Vonderhaar (1987). Role of serum in prolactin responsiveness of MCF-7 human breast cancer cells in long term tissue culture. Cancer Res. 47:3509–3514.

    Google Scholar 

  16. R. Das, E. Ginsburg, and B. K. Vonderhaar (1994). Tamoxifen as an antilactogen in human breast cancer cells. In R. S. Rao, M. G. Deo, L. D. Sanghvi, and I. Mittra (eds.), Proceedings of the International Cancer Congress, Monduzzi Editore, Bologna, pp. 1487–1491.

    Google Scholar 

  17. A. Lemus-Wilson, P. A. Kelly, and D. E. Blask (1995). Melatonin blocks the stimulatory effects of prolactin on human breast cancer cell growth in culture. British J. Cancer 72:1435–1440.

    Google Scholar 

  18. H. A. Lochnan, H. Buteau, S. Richards, M. Edery, and P. A. Kelley (1995). Functional activity of the human prolactin receptor and its ligands. Mol. Cell. Endocrinol. 114:91–99.

    Google Scholar 

  19. N. E. Hynes, N. Cella, and M. Wartmann (1997). Prolactin mediated intracellular signaling in mammary epithelial cells. J. Mam. Gland Biol. Neoplasia 2(1):19–27.

    Google Scholar 

  20. J. R. Wicks and C. L. Brooks (1995). Biological activity of phosphorylated and dephosphorylated bovine prolactin. Mol. Cell. Endocrinol. 112:223–229.

    Google Scholar 

  21. T. Hoffman, C. Penel, and C. Ronin (1993). Glycosylation of human prolactin regulates hormone bioactivity and metabolic clearance. J. Endocrinol. Invest. 16:807–816.

    Google Scholar 

  22. A. E. Price, K. B. Loginenko, E. A. Higgins, E. S. Cole, and S. Richards (1995). Studies on the microheterogeneity and in vitro activity of glycosylated and nonglycosylated recombinant human prolactin separated using a novel purification process. Endocrinology 136:4827–4833.

    Google Scholar 

  23. L. Lesueur, M. Edery, S. Ali, J. Paly, P. A. Kelly, and J. Djiane (1991). Comparison of long and short forms of the prolactin receptor on prolactin-induced milk protein gene transcription. Proc. Natl. Acad. Sci. U.S.A. 88:824–828.

    Google Scholar 

  24. C. V. Clevenger, W. P. Chang, W. Ngo, T. L. M. Pasha, K. T. Montone, and J. E. Tomaszewski (1995). Expression of prolactin and prolactin receptor in human breast carcinoma. Am. J. Pathol. 146:695–705.

    Google Scholar 

  25. V. Goffin and P. A. Kelly (1997). The prolactin/growth hormone receptor family: Structure/function relationships. J. Mam. Gland Biol. Neoplasia 2(1):7–17.

    Google Scholar 

  26. K. D. O'Neal and L.-Y. Yu-Lee (1994). Differential signal transduction of the short, Nb2, and long prolactin receptors. J. Biol. Chem. 269:26076–26082.

    Google Scholar 

  27. R. Das and B. K. Vonderhaar (1995). Transduction of prolactin's growth signal through both the long and short forms of the prolactin receptor. Mol. Endocrinol. 9:1750–1759.

    Google Scholar 

  28. H. Rui, R. A. Kirken, and W. L. Farrar (1994). Activation of receptor-associated tyrosine kinase JAK2 by prolactin. J. Biol. Chem. 269:5364–5368.

    Google Scholar 

  29. G. S. Campbell, L. S. Argetsinger, J. N. Ihle, P. A. Kelly, J. A. Rillema, and C. Carter-Su (1994). Activation of JAK (JAK2) tyrosine kinase by prolactin receptors in NB (NB2) cells and mouse mammary gland explants. Proc. Natl. Acad. Sci. U.S.A. 91:5232–5236.

    Google Scholar 

  30. I. Dusanter-Fourt, O. Muller, A. Ziemiecki, P. Mayeux, B. Drucker, J. Djiane, A. Wilks, A. G. Harpur, S. Fischer, and S. Gisselbrecht (1994). Identification of JAK protein tyrosine kinases as signaling molecules for prolactin. Functional analysis of prolactin receptor and prolactin-erythropoietin receptor chimera expressed in lymphoid cells. EMBO J. 13:2583–2591.

    Google Scholar 

  31. M. J. Waters, N. Daniel, C. Bignon, and J. Dijiane (1995). The rabbit mammary gland prolactin receptor is tyrosine phosphorylated in response to prolactin in vivo and in vitro. J. Biol. Chem. 270:5136–5143.

    Google Scholar 

  32. L. DaSilva, H. Rui, R. A. Erwin, O. M. Z. Howard, R. A. Kirken, M. G. Malabarba, R. H. Hackett, A. Larner, and W. L. Farrar (1996). Prolactin recruits STAT1, STAT3, and STAT5 independent of conserved receptor tyrosine TYR402, TYR479, TYR515, and TYR580. Mol. Cell. Endocrinol. 117:131–140.

    Google Scholar 

  33. H. Wakao, F. Gouilleux, and B. Groner (1994). Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. EMBO J. 13:2182–2191.

    Google Scholar 

  34. X. Liu, G. W. Robinson, F. Gouilleux, B. Groner, and L. Hennighausen (1995). Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue. Proc. Natl. Acad. Sci. U.S.A. 92:8831–8835.

    Google Scholar 

  35. M. David, E. F. Petricoin, K. I. Igarashi, G. M. Feldman, D. S. Finbloom, and A. C. Larner (1994). Prolactin activates the interferon-regulated p91 transcription factor and the JAK2 kinase by tyrosine phosphorylation. Proc. Natl. Acad. Sci. U.S.A. 91:7174–7178.

    Google Scholar 

  36. R. Das and B. K. Vonderhaar (1996). Involvement of SHC, Grb2, Sos, and ras in prolactin signal transduction in mammary cells. Oncogene 13:1139–1145.

    Google Scholar 

  37. J. E. Darnell Jr., I. M. Kerr, and G. R. Stark (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–1421.

    Google Scholar 

  38. J. J. Berlanga, J. A. F. Vara, J. Martin-Perez, and J. P. Garcia-Ruiz (1995). Prolactin receptor is associated with c-src kinase in rat liver. Mol. Endocrinol. 9:1461–1467.

    Google Scholar 

  39. C. V. Clevenger and M. V. Medaglia (1994). The protein tyrosine kinase p59fyn is associated with prolactin (PRL) receptor and is activated by PRL stimulation of T-lymphocytes. Mol. Endocrinol. 8:674–681.

    Google Scholar 

  40. C. V. Clevenger, W. Ngo, D. L. Sokol, S. M. Luger, and A. M. Gewirtz (1995). Vav is necessary for prolactin-stimulated proliferation and is translocated into the nucleus of a T-cell line. J. Biol. Chem. 270:13246–13253.

    Google Scholar 

  41. S. Ali, Z. Chen, J.-J. Lebrun, W. Vogel, A. Kharitonenkov, P. Kelly, and A. Ullrich (1996). PTP1D is a positive regulator of the prolactin signal leading to β-casein promoter activation. EMBO J. 15:135–142.

    Google Scholar 

  42. N. Daniel, M. J. Waters, C. Bignon, and J. Djiane (1996). Involvement of a subset of tyrosine kinases and phosphatases in regulation of the β-lactoglobulin gene promoter by prolactin. Mol. Cell. Endocrinol. 118:25–35.

    Google Scholar 

  43. M. Bayat-Sarmadi, C. Puissant, and L. M. Houdebine (1995). The effects of various kinase and phosphatase inhibitors on the transmission of the prolactin and extracellular matrix signals to rabbit α-S1-casein and transferrin genes. Int. J. Biochem. Cell. Biol. 27:707–718.

    Google Scholar 

  44. R. A. Erwin, R. A. Kirken, M. G. Malabarba, W. L. Farrar, and H. Rui (1995). Prolactin activates Ras via signaling proteins SHC, growth factor receptor bound 2 and son of sevenless. Endocrinology 136:3512–3518.

    Google Scholar 

  45. G. Elberg, M. J. Rapoport, D. Vashdi-Elberg, A. Gertler, and Y. Scechter (1996). Lactogenic hormones rapidly activate p21 ras/mitogen-activated protein kinase in Nb2-11C rat lymphoma cells. Endocrine 4:65–71.

    Google Scholar 

  46. R. Das and B. K. Vonderhaar (1996). Activation of raf-1, MEK, and MAP kinase in prolactin responsive mammary cells. Breast Cancer Res. Treat. 40:141–149.

    Google Scholar 

  47. C. V. Clevenger, T. Torigoe, and J. C. Reed (1994). Prolactin induces rapid phosphorylation and activation of prolactin receptor-associated Raf-1 kinase in a T-cell line. J. Biol. Chem. 269:5559–5565.

    Google Scholar 

  48. R. Piccoletti, P. Maroni, P. Bendinelli, and A. Bernelli-Zazzera (1994). Rapid stimulation of mitogen-activated protein kinase of rat liver by prolactin. Biochem. J. 303:429–433.

    Google Scholar 

  49. A. R. Buckley, Y. P. Rao, D. J. Buckley, and P. W. Gout (1994). Prolactin-induced phosphorylation and nuclear translocation of MAP kinase in Nb2 lymphoma cells. Biochem. Biophys. Res. Commun. 204:1158–1164.

    Google Scholar 

  50. S. Ganguli, L. Hu, P. Menke, R. J. Collier, and A. Gertler (1996). Nuclear accumulation of multiple protein kinases during prolactin induced proliferation of Nb2 rat lymphoma cells. J. Cell. Physiol. 167:251–260.

    Google Scholar 

  51. G. B. Carey and J. P. Liberti (1995). Stimulation of receptor-associated kinase, tyrosine kinase, and MAP kinase is required for prolactin-mediated macromolecular biosynthesis and mitogenesis in Nb2 lymphoma. Archive Biochem. Biophys. 316:179–189.

    Google Scholar 

  52. S. C. Kiley, J. Welsh, C. J. Narvaez, and S. Jaken (1996). Protein kinase C isozymes and substrates in mammary carcinogenesis. J. Mam. Gland Biol. Neoplasia 1:177–187.

    Google Scholar 

  53. J. A. Rillema, L. Y. Wing, and K. A. Foley (1983). Effects of phospholipases on ornithine decarboxylase activity in mammary gland explants from midpregnancy mice. Endocrinology 113:2024–2028.

    Google Scholar 

  54. A. R. Buckley, D. W. Montgomery, R. Kibler, C. W. Putnam, C. F. Zukoski, P. W. Gout, C. T. Beer, and D. H. Russell (1986). Prolactin stimulation of ornithine decarboxylase and mitogenesis in Nb2 node lymphoma cells: the role of protein kinase C and calcium mobilization. Immunopharm. 12:37–51.

    Google Scholar 

  55. J. A. Rillema, S. B. Waters, and T. M. Tarrant (1989). Studies on the possible role of protein kinase C in the prolactin regulation of cell replication in Nb2 node lymphoma cells. Proc. Soc. Exp. Biol. 192:140–144.

    Google Scholar 

  56. S. B. Waters and J. A. Rillema (1989). Role of protein kinase C in the prolactin-induced responses in mouse mammary gland explants. Mol. Cell. Endocrinol. 63:159–166.

    Google Scholar 

  57. A. R. Buckley, P. D. Crowe, and D. H. Russell (1988). Rapid activation of protein kinase C in isolated rat liver nuclei by prolactin. Proc. Natl. Acad. Sci. U.S.A. 85:8649–8653.

    Google Scholar 

  58. B. Marquardt, D. Frith, and S. Stabel (1994). Signaling from TPA to MAP kinase requires protein kinase C, raf, and MEK: reconstitution of the signaling pathway in vitro. Oncogene 9:3213–3218.

    Google Scholar 

  59. J. VanderKuur, G. Allevato, N. Billestrup, G. Norstedt, and C. Carter-Su (1995). Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2. J. Biol. Chem. 270:7587–7593.

    Google Scholar 

  60. M. David, E. Petricoin III, C. Benjamin, R. Pine, M. J. Weber, and A. C. Larner (1995). Requirement for MAP Kinase (ERK2) activity in Interferon α-and interferon β-stimulated gene expression through STAT proteins. Science 269:1721–1723.

    Google Scholar 

  61. X. Zhang, J. Blenis, H. C. Li, C. Schindler, and S. Chen-kiang (1995). Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science 267:1990–1994.

    Google Scholar 

  62. M. T. Zabala and J. P. Garcia-Ruiz (1989). Regulation of expression of the messenger ribonucleic acid encoding the cytosolic form of phosphoenolpyruvate carboxykinase in liver and small intestine of lactating rats. Endocrinology 125:2587–2593.

    Google Scholar 

  63. A. R. Buckley, D. J. Buckley, M. A. Leff, D. S. Hoover, and N. S. Magnuson (1995). Rapid induction of pim-1 expression by prolactin and interleukin-2 in rat Nb2 lymphoma cells. Endocrinology 136:5252–5259.

    Google Scholar 

  64. A. N. Stevens, Y. Wang, K. A. Sieger, H.-F. Lu, and L. Y. Yu-Lee (1995). Biphasic transcription regulation of the interferon regulatory factor-1 gene by prolactin: Involvement of γ-Interferon-activated sequence and stat-related proteins. Mol. Endocrinol. 9:513–525.

    Google Scholar 

  65. E. A. Musgrove, R. Hui, K. J. E. Sweeney, C. K. W. Watts, and R. L. Sutherland (1996). Cyclins and breast cancer. J. Mam. Gland Biol. Neoplasia 1:153–162.

    Google Scholar 

  66. P. Sicinski, J. L. Donaher, S. B. Parker, T. Li, A. Fazeli, H. Gardner, S. Z. Haslam, R. T. Bronson, S. J. Elledge, and R. A. Weinberg (1995). Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621–630.

    Google Scholar 

  67. Y. Hosokawa, T. Onga, and K. Nakashima (1994). Induction of D2 and D3 cyclin-encoding genes during promotion of the G1/S transition by prolactin in rat Nb2 cells. Gene 147:249–252.

    Google Scholar 

  68. T. C. Wang, R. D. Cardiff, L. Zukerberg, E. Lees, A. Arnold, and E. V. Schmidt (1994). Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369:669–671.

    Google Scholar 

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Das, R., Vonderhaar, B.K. Prolactin as a Mitogen in Mammary Cells. J Mammary Gland Biol Neoplasia 2, 29–39 (1997). https://doi.org/10.1023/A:1026369412612

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