Signaling and antiproliferative effects of type I and II gonadotropin-releasing hormone receptors in breast cancer cells

Ann R Finch, Lisa Green, James N Hislop, Eamonn Kelly, Craig A McArdle

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

GnRH receptors (GnRH-Rs) mediate direct antiproliferative effects on hormone-dependent cancer cells. GnRH-Rs can be grouped according to ligand specificity (for GnRH-I and -II), and there is evidence that type II GnRH ligands and/or receptors can inhibit proliferation. Type I GnRH-Rs (e.g. human and sheep) lack the C-terminal tails found in other G protein-coupled receptors including type II GnRH-Rs (e.g. Xenopus; XGnRH-R). This underlies the remarkable resistance of type I GnRH-Rs to desensitization and may be important for chronic effects on proliferation. To test this, we have compared the antiproliferative effects of GnRH-Rs expressed in MCF7 breast cancer cells using recombinant adenovirus (Ad). Endogenous GnRH-Rs were not detected, but infection with Ad-expressing sheep GnRH-Rs (sGnRH-R) facilitated proliferation inhibition by Buserelin, and maximum inhibition required only 10,000-20,000 sGnRH-Rs. XGnRH-Rs were much less efficient at inhibiting proliferation and were internalized faster than sGnRH-Rs. Thus, the type II GnRH-R is less efficient at inhibiting proliferation, presumably because it is rapidly desensitized and/or internalized. Moreover, comparisons of human GnRH-R, sGnRH-R, and XGnRH-R, as well as chimeric receptors (type I GnRH-Rs with C-terminal tails from XGnRH-Rs), revealed that C-terminal tail addition increases receptor expression and thereby increases the efficiency with which the vector facilitates the antiproliferative effect.
Original languageEnglish
Pages (from-to)1823-32
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume89
Issue number4
DOIs
Publication statusPublished - Apr 2004

Keywords

  • Animals
  • Antineoplastic Agents, Hormonal
  • Breast Neoplasms
  • Buserelin
  • Cell Division
  • Cell Line, Tumor
  • Chimera
  • Female
  • Gene Transfer Techniques
  • Humans
  • Molecular Conformation
  • Peptide Fragments
  • Receptors, LHRH
  • Sheep
  • Signal Transduction
  • Species Specificity
  • Xenopus laevis

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