Epidermal growth factor induces G protein-coupled receptor 30 expression in estrogen receptor-negative breast cancer cells.
Different cellular receptors mediate the biological effects induced by estrogens. In addition to the classical nuclear estrogen receptors (ERs)-alpha and -beta, estrogen also signals through the seven-transmembrane G-protein-coupled receptor (GPR)-30. Using as a model system SkBr3 and BT20 breast cancer cells lacking the classical ER, the regulation of GPR30 expression by 17beta-estradiol, the selective GPR30 ligand G-1, IGF-I, and epidermal growth factor (EGF) was evaluated. Transient transfections with an expression plasmid encoding a short 5'-flanking sequence of the GPR30 gene revealed that an activator protein-1 site located within this region is required for the activating potential exhibited only by EGF. Accordingly, EGF up-regulated GPR30 protein levels, which accumulated predominantly in the intracellular compartment. The stimulatory role elicited by EGF on GPR30 expression was triggered through rapid ERK phosphorylation and c-fos induction, which was strongly recruited to the activator protein-1 site found in the short 5'-flanking sequence of the GPR30 gene. Of note, EGF activating the EGF receptor-MAPK transduction pathway stimulated a regulatory loop that subsequently engaged estrogen through GPR30 to boost the proliferation of SkBr3 and BT20 breast tumor cells. The up-regulation of GPR30 by ligand-activated EGF receptor-MAPK signaling provides new insight into the well-known estrogen and EGF cross talk, which, as largely reported, contributes to breast cancer progression. On the basis of our results, the action of EGF may include the up-regulation of GPR30 in facilitating a stimulatory role of estrogen, even in ER-negative breast tumor cells.
Albanito
Lidia
L
Department Pharmaco-Biology, University of Calabria, 87030 Rende (Cosenze), Italy.
Sisci
Diego
D
Aquila
Saveria
S
Brunelli
Elvira
E
Vivacqua
Adele
A
Madeo
Antonio
A
Lappano
Rosamaria
R
Pandey
Deo Prakash
DP
Picard
Didier
D
Mauro
Loredana
L
Andò
Sebastiano
S
Maggiolini
Marcello
M
D024506:5' Flanking Region / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D011960:Receptors, Estrogen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D018808:Transcription Factor AP-1; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases