G Protein-Coupled Receptor 30 Expression Is Up-Regulated by EGF and TGFα in Estrogen Receptor α-Positive Cancer Cells

In the present study, we evaluated the regulation of G protein-coupled receptor (GPR)30 expression in estrogen receptor (ER)-positive endometrial, ovarian, and estrogen-sensitive, as well as tamoxifen-resistant breast cancer cells. We demonstrate that epidermal growth factor (EGF) and TGFα transacti...

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Bibliographic Details
Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2009-11, Vol.23 (11), p.1815-1826
Main Authors: Vivacqua, Adele, Lappano, Rosamaria, De Marco, Paola, Sisci, Diego, Aquila, Saveria, De Amicis, Francesca, Fuqua, Suzanne A. W, Andò, Sebastiano, Maggiolini, Marcello
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Estrogen Receptor alpha - biosynthesis
Gene Expression Regulation, Neoplastic
Humans
Models, Biological
Original Research
Phosphorylation
Promoter Regions, Genetic
Proto-Oncogene Proteins c-fos - metabolism
Receptors, Estrogen
Receptors, G-Protein-Coupled - biosynthesis
Signal Transduction
Transcription Factor AP-1 - metabolism
Transcriptional Activation
Transforming Growth Factor alpha - biosynthesis
Tyrosine - chemistry
Up-Regulation
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Summary:In the present study, we evaluated the regulation of G protein-coupled receptor (GPR)30 expression in estrogen receptor (ER)-positive endometrial, ovarian, and estrogen-sensitive, as well as tamoxifen-resistant breast cancer cells. We demonstrate that epidermal growth factor (EGF) and TGFα transactivate the GPR30 promoter and accordingly up-regulate GPR30 mRNA and protein levels only in endometrial and tamoxifen-resistant breast cancer cells. These effects exerted by EGF and TGFα were dependent on EGF receptor (EGFR) expression and activation and involved phosphorylation of the Tyr1045 and Tyr1173 EGFR sites. Using gene-silencing experiments and specific pharmacological inhibitors, we have ascertained that EGF and TGFα induce GPR30 expression through the EGFR/ERK transduction pathway, and the recruitment of c-fos to the activator protein-1 site located within GPR30 promoter sequence. Interestingly, we show that functional cross talk of GPR30 with both activated EGFR and ERα relies on a physical interaction among these receptors, further extending the potential of estrogen to trigger a complex stimulatory signaling network in hormone-sensitive tumors. Given that EGFR/HER2 overexpression is associated with tamoxifen resistance, our data may suggest that ligand-activated EGFR could contribute to the failure of tamoxifen therapy also by up-regulating GPR30, which in turn could facilitates the action of estrogen. In addition, important for resistance is the ability of tamoxifen to bind to and activate GPR30, the expression of which is up-regulated by EGFR activation. Our results emphasize the need for new endocrine agents able to block widespread actions of estrogen without exerting any stimulatory activity on transduction pathways shared by the steroid and growth factor-signaling networks. EGF and TGFα generate a stimulatory network in estrogen-sensitive cancer cells up-regulating GPR30, which interacts with activated EGFR and ERα.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2009-0120