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This version published online on October 20, 2005
Molecular Endocrinology, doi:10.1210/me.2005-0280
A more recent version of this article appeared on March 1, 2006
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Submitted on July 8, 2005
Accepted on October 11, 2005

THE G PROTEIN-COUPLED RECEPTOR GPR30 MEDIATES THE PROLIFERATIVE EFFECTS INDUCED BY 17{beta}-ESTRADIOL AND HYDROXYTAMOXIFEN IN ENDOMETRIAL CANCER CELLS

Adele Vivacqua, Daniela Bonofiglio, Anna Grazia Recchia, Anna Maria Musti, Didier Picard, Sebastiano Andò, and Marcello Maggiolini*

Dept. Pharmaco-Biology and Dept. Cellular Biology, University of Calabria, 87030 Rende (CS), Italy. Dept. Cellular Biology, University of Genève

* To whom correspondence should be addressed. E-mail: marcellomaggiolini{at}yahoo.it.

The growth of both normal and transformed epithelial cells of the female reproductive system is stimulated by estrogens mainly through the activation of the estrogen receptor (ER) a, which is a ligand-regulated transcription factor. The selective ER modulator tamoxifen (TAM) has been widely used as an ER antagonist in breast tumor, however long-term treatment is associated with an increased risk of endometrial cancer. To provide new insights into the potential mechanisms involved in the agonistic activity exerted by TAM in the uterus, we have first evaluated the potential of 4-hydroxytamoxifen (OHT), the active metabolite of TAM, to transactivate the wild-type ER{alpha} and its splice variant expressed in Ishikawa and HEC1A endometrial tumor cells, respectively. OHT was able to antagonize only the activation of ER{alpha} by E2 in Ishikawa cells, whereas it upregulated c-fos expression in a rapid manner similar to E2 and independently of ER{alpha} in both cell lines. This stimulation occurred through the G protein-coupled receptor (GPCR) named GPR30 and required Src-related and EGF receptor tyrosine kinase activities, along with the activation of both ERK1/2 and PI3K/AKT pathways. Most importantly, OHT like E2 stimulated the proliferation of Ishikawa as well as HEC1A cells. Transfecting a GPR30 antisense expression vector in both endometrial cancer cell lines, OHT was no longer able to induce growth effects while the proliferative response to E2 was completely abrogated only in HEC1A cells. Furthermore, in presence of the inhibitors of MAPK and PI3K pathways, PD 98059 and wortmannin respectively, E2 and OHT did not elicit growth stimulation. Our data demonstrate a new mode of action of E2 and OHT in endometrial cancer cells, contributing to a better understanding of the molecular mechanisms involved in their uterine agonistic activity.
Key words: GPR30 • estrogen receptor • 17b-estradiol • hydroxytamoxifen • c-fos • endometrial cancer cells

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ  |  PR
Ligands:   Dexamethasone  |  17β-Estradiol  |  Dihydrotestosterone  |  Progesterone  |  4-Hydroxytamoxifen



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