Skip to main content

Advertisement

Log in

Effects of estrogen receptor antagonist on biological behavior and expression of growth factors in the prolactinoma MMQ cell line

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

The relationship between estrogen and pituitary prolactinoma is well documented. The biological effects of estrogen are mainly mediated by estrogen receptor α (ERα). Several lines of evidence demonstrate that growth factors such as pituitary tumor transforming gene (PTTG), basic fibroblast growth factor (bFGF), transforming growth factor β1 (TGFβ1), transforming growth factor β3 (TGFβ3), and transforming growth factor β receptor type II (TGFβRII) play an important role in prolactinoma pathogenesis induced by estrogen, but the relationship between ERα and such growth factors is still unclear. The aims of this study are to investigate the functional role of ERα in proliferation, prolactin (PRL) secretion, and expression of the above-mentioned growth factors in MMQ cells in the absence of estrogen and to discuss the feasibility of using an estrogen receptor antagonist to treat prolactinoma. Fulvestrant, a “pure” antiestrogen without any estrogen-like activity, was used to block expression of ERα in the MMQ cell line. Proliferation and PRL secretion of MMQ cells were measured using CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS) and the enzyme-linked immunosorbent assay (ELISA) method. Levels of ERα, PTTG, bFGF, TGFβ1, TGFβ3, and TGFβRII were analyzed by real-time polymerase chain reaction (PCR) and Western blot. Fulvestrant significantly inhibited cell proliferation (up to 60.80%) and PRL secretion (up to 77.95%), and changed expression of TGFβ3 and TGFβRII in the absence of estrogen. In conclusion, ERα plays an important functional role in proliferation and PRL secretion of pituitary prolactinomas and also can change expression of some growth factors even under the condition of no estrogen. Fulvestrant could potentially be an effective therapy for treating such tumors.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Yin P, Arita J (2000) Differential regulation of prolactin release and lactotrope proliferation during pregnancy, lactation and the estrous cycle. Neuroendocrinology 72:72–79

    Article  PubMed  CAS  Google Scholar 

  2. Lloyd RV (1983) Estrogen-induced hyperplasia and neoplasia in the rat anterior pituitary gland. An immunohistochemical study. Am J Pathol 113:198–206

    PubMed  CAS  Google Scholar 

  3. Molitch ME (1999) Management of prolactinomas during pregnancy. J Reprod Med 44(12 Suppl):1121–1126

    PubMed  CAS  Google Scholar 

  4. Carol W, Lauterbach H, Klinger G, Unger A, Michels W (1988) Prolactin stimulation using the metoclopramide test in females taking oral contraceptives. Zentralbl Gynakol 110:1515–1521 (in German)

    PubMed  CAS  Google Scholar 

  5. Shy KK, McTiernan AM, Daling JR, Weiss NS (1983) Oral contraceptive use and the occurrence of pituitary prolactinoma. JAMA 249:2204–2207

    Article  PubMed  CAS  Google Scholar 

  6. Elias KA, Weiner RI (1984) Direct arterial vascularization of estrogen-induced prolactin-secreting anterior pituitary tumors. Proc Natl Acad Sci U S A 81:4549–4553

    Article  PubMed  CAS  Google Scholar 

  7. Raymond V, Beaulieu M, Labrie F, Boissier J (1978) Potent antidopaminergic activity of estradiol at the pituitary level on prolactin release. Science 200:1173–1175

    Article  PubMed  CAS  Google Scholar 

  8. Sarkar Dk, Hentges ST, De A, Reddy RH (1998) Hormonal control of pituitary prolactin-secreting tumors. Front Biosci 3:d934–d943

    PubMed  CAS  Google Scholar 

  9. Mosselman S, Polman J, Dijkema R (1996) ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett 392:49–53

    Article  PubMed  CAS  Google Scholar 

  10. Le Goff P, Montano MM, Schodin DJ, Katzenellenbogen BS (1994) Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity. J Biol Chem 269:4458–4466

    PubMed  CAS  Google Scholar 

  11. Aronica SM, Katzenellenbogen BS (1991) Progestrone receptor regulation in uterine cells: stimulation by estrogen, cyclic adenosine 3′,5′-monophosphate, and insulin-like growth factor I and supression by antiestrogens and protein kinase inhibitors. Endocrinology 128:2045–2052

    Article  PubMed  CAS  Google Scholar 

  12. Beck CA, Weigel NL, Edwards DP (1992) Effects of hormone and cellular modulators of protein phosphorylation on transcriptional activity, DNA binding, and phosphorylation of human progesterone receptors. Mol Endocrinol 6:607–620

    Article  PubMed  CAS  Google Scholar 

  13. Sirbasku DA (1978) Estrogen induction of growth factors specific for hormone-responsive mammary, pituitary and kidney tumor cells. Proc Natl Acad Sci U S A 75:3786–3790

    Article  PubMed  CAS  Google Scholar 

  14. Soto AM, Sonnenschein C (1987) Cell proliferation of estrogen-sensitive cells: the case for negative control. Endocr Rev 8:44–52

    Article  PubMed  CAS  Google Scholar 

  15. Judd AM, Login IS, Kovacs K, Ross PC, Spangelo BL, Jarvis WD, MacLeod RM (1988) Characterization of the MMQ cell, a prolactin-secreting clonal cell line that is responsive to dopamine. Endocrinology 123:2341–2350

    Article  PubMed  CAS  Google Scholar 

  16. Wakeling AE, Dukes M, Bowler J (1991) A potent specific pure antiestrogen with clinical potential. Cancer Res 51:3867–3873

    PubMed  CAS  Google Scholar 

  17. Lykkesfeldt AE, Madsen MW, Briand P (1994) Altered expression of estrogen-regulated genes in a tamoxifen-resistant and ICI 164, 384 and ICI 182, 780 sensitive human breast cancer cell line, MCF-7/TAMR-1. Cancer Res 54:1587–1595

    PubMed  CAS  Google Scholar 

  18. Gottardis MM, Jiang SY, Jeng MH, Jordan VC (1989) Inhibition of tamoxifen-stimulated growth of an MCF-7 tumor variant in athymic mice by novel steroidal antiestrogens. Cancer Res 49:4090–4093

    PubMed  CAS  Google Scholar 

  19. Bross PF, Baird A, Chen G, Jee JM, Lostritto RT, Morse DE, Rosario LA, Williams GM, Yang P, Rahman A, Williams G, Pazdur R (2003) Fulvestrant in postmenopausal women with advanced breast cancer. Clin Cancer Res 9:4309–4317

    PubMed  CAS  Google Scholar 

  20. Fawell SE, White R, Hoare S, Sydenham M, Page M, Parker MG (1990) Inhibition of estrogen receptor-DNA binding by the “pure” antiestrogen ICI 164, 384 appears to be mediated by impaired receptor dimerization. Proc Natl Acad Sci U S A 87:6883–6887

    Article  PubMed  CAS  Google Scholar 

  21. Ignar-Trowbridge DM, Teng CT, Ross KA, Parker MG, Korach KS, McLachlan JA (1993) Peptide growth factors elicit estrogen receptor-dependent transcriptional activation of an estrogen-responsive element. Mol Endocrinol 7:992–998

    Article  PubMed  CAS  Google Scholar 

  22. Improta-Brears T, Whorton AR, Codazzi F, York JD, Meyer T, McDonnell DP (1999) Estrogen-induced activation of mitogen-activated protein kinase requires mobilization of intracellular calcium. Proc Natl Acad Sci U S A 96:4686–4691

    Article  PubMed  CAS  Google Scholar 

  23. Cenni B, Picard D (1999) Ligand-independent activation of steroid receptors: new roles for old players. Trends Endocrinol Metab 10:41–46

    Article  PubMed  CAS  Google Scholar 

  24. El-Tanani MK, Green CD (1997) Two separate mechanisms for ligand-independent activation of the estrogen receptor. Mol Endocrinol 11:928–937

    Article  PubMed  CAS  Google Scholar 

  25. Heaney AP, Singson R, McCabe CJ, Nelson V, Nakashima M, Melmed S (2000) Pituitary-tumour transforming gene in colorectal tumors. Lancet 355:712–715

    Article  Google Scholar 

  26. Heaney AP, Horwitz GA, Wang Z, Singson R, Melmed S (1999) Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis. Nat Med 5:1317–1321

    Article  PubMed  CAS  Google Scholar 

  27. Amano O, Yoshitake Y, Nishikawa K, Iseki S (1993) Immunocytochemical localization of basic fibroblast growth factor in the rat pituitary gland. Arch Histol Cytol 56:269–276

    Article  PubMed  CAS  Google Scholar 

  28. Elias KA, Weiner RI (1984) Direct arterial vascularization of estrogen-induced prolactin-secreting anterior pituitary tumors. Proc Natl Acad Sci U S A 81:4549–4553

    Article  PubMed  CAS  Google Scholar 

  29. Chaturvedi K, Sarkar DK (2004) Involvement of protein kinase C-dependent mitogen-activated protein kinase p44/42 signaling pathway for cross-talk between estradiol and transforming growth factor-beta3 in increasing basic fibroblast growth factor in folliculostellate cells. Endocrinology 145:706–715

    Article  PubMed  CAS  Google Scholar 

  30. Pastorcic M, De A, Boyadjieva N, Vale W, Sarkar DK (1995) Reduction in the expression and action of transforming growth factor β1 on lactotropes during estrogen-induced tumorigenesis in the anterior pituitary. Cancer Res 55:4892–4898

    PubMed  CAS  Google Scholar 

  31. Minami S, Sarkar DK (1997) Transforming growth factor-β1 inhibits prolactin secretion and lactotropic cell proliferation in the pituitary of estrogen-treated Fischer 344 rats. Neurochem Int 30:499–506

    Article  PubMed  CAS  Google Scholar 

  32. Hentges S, Boyadjieva N, Sarkar DK (2000) Transforming growth factor-β3 stimulates lactotrope cell growth by increasing basic fibroblast growth factor from folliculo-stellate cells. Endocrinology 141:859–867

    Article  PubMed  CAS  Google Scholar 

  33. Brattain MG, Markowitz SD, Willson JKV (1996) The type II transforming growth factor-βreceptor as a tumor-suppressor gene. Curr Opin Oncol 8:49–53

    Article  PubMed  CAS  Google Scholar 

  34. Sarkar DK, Pastorcic M, De A, Engel M, Moses H, Ghasemzadeh B (1998) Role of transforming growth factor (TGF)-βtype I and TGF-β type II receptors in the TGF-β1-regulated gene expression in pituitary prolactin-secreting lactotropes. Endocrinology 139:3620–3628

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yazhuo Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lv, H., Li, C., Gui, S. et al. Effects of estrogen receptor antagonist on biological behavior and expression of growth factors in the prolactinoma MMQ cell line. J Neurooncol 102, 237–245 (2011). https://doi.org/10.1007/s11060-010-0326-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-010-0326-2

Keywords

Navigation