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Signaling and Antiproliferative Effects Mediated by GnRH Receptors After Expression in Breast Cancer Cells Using Recombinant Adenovirus

University Research Center for Neuroendocrinology, University of Bristol, Bristol, United Kingdom BS2 8HW; Medical Research Council Human Reproductive Science Unit, Center for Reproductive Biology (R.P.M.), Edinburgh, United Kingdom EH3 9ET

Address all correspondence and requests for reprints to: Dr. Craig A McArdle, University Research Center for Neuroendocrinology, University of Bristol, Bristol, United Kingdom BS2 8HW. E-mail: craig.mcardle{at}bris.ac.uk

GnRH receptors (GnRH-Rs) are found in human cancers, including those of the breast, and GnRH can inhibit the growth of cell lines derived from such cancers. Although pituitary and extrapituitary GnRH-R transcripts appear identical, their functional characteristics may differ. Most extrapituitary GnRH-Rs have low affinity for GnRH analogs and may not activate PLC or discriminate between agonists and antagonists in the same way as pituitary GnRH-Rs. Here we have assessed whether GnRH-Rs expressed exogenously in breast cancer cells differ from those in gonadotropes. We found no evidence for endogenous GnRH-Rs in MCF7 cells, but after infection with adenovirus expressing the GnRH-R (Ad GnRH-R) at a multiplicity of infection of 10 or greater, at least 80% expressed GnRH-Rs. These had high affinity (K_d for [¹²⁵I]buserelin, 1.4 nM) and specificity (rank order of potency, buserelin>GnRH>>chicken GnRH-II) and mediated stimulation of [³H]IP accumulation. Increasing viral titer [from multiplicity of infection, 3–300] increased receptor number (10,000–225,000 sites/cell) and [³H]IP responses. GnRH stimulated ERK2 phosphorylation in Ad GnRH-R-infected cells, and this effect, like stimulation of [³H]IP accumulation, was blocked by GnRH-R antagonists. GnRH also inhibited [³H]thymidine incorporation into Ad GnRH-R-infected cells (but not control cells). This effect was mimicked by agonist analogs and inhibited by two antagonists. Thus, when exogenous GnRH-Rs are expressed at density comparable to that in gonadotropes, they are functionally indistinguishable from the endogenous GnRH-Rs in gonadotropes, and increasing expression of high affinity GnRH-Rs can dramatically enhance the direct antiproliferative effect of GnRH agonists on breast cancer cells.

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