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Signaling and Antiproliferative Effects of Type I and II Gonadotropin-Releasing Hormone Receptors in Breast Cancer Cells

Wellcome Laboratories for Integrative Neuroscience and Endocrinology (A.R.F., L.G., C.A.M.) and Department of Pharmacology (E.K.), University of Bristol, Bristol, BS1 3NY, United Kingdom; and University of California at San Francisco (J.N.H.), San Francisco, California 94143

Address all correspondence and requests for reprints to: Dr. Craig A. McArdle, Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Whitson Street, Bristol, BS1 3NY United Kingdom. E-mail: craig.mcardle{at}bris.ac.uk.

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.

This work was supported by the Wellcome Trust for project grant support (062918).

Abbreviations: [³H]IP_x, [³H]Inositol phosphate; Ad, adenovirus; AR, adrenergic receptor; cGnRH-II, chicken GnRH-II; FCS, fetal calf serum; GnRH-R, GnRH receptor; GPCR, G protein-coupled receptors; hGnRH-R, human GnRH-R; h.XGnRH-R, hGnRH-R with an added XGnRH-R C-terminal tail; PLC, phospholipase C; PSS, physiological salt solution; sGnRH-R, sheep GnRH-R; s.XGnRH-R, sGnRH-R with an added XGnRH-R C-terminal tail; XGnRH-R, Xenopus GnRH-R.

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