RT Journal Article
SR Electronic
T1 17-β-Estradiol Inhibits Transforming Growth Factor-β Signaling and Function in Breast Cancer Cells via Activation of Extracellular Signal-Regulated Kinase through the G Protein-Coupled Receptor 30
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1533
OP 1543
DO 10.1124/mol.108.046854
VO 74
IS 6
A1 Burkhard Kleuser
A1 Daniela Malek
A1 Ronald Gust
A1 Heinz H. Pertz
A1 Henrik Potteck
YR 2008
UL http://molpharm.aspetjournals.org/content/74/6/1533.abstract
AB Breast cancer development and breast cancer progression involves the deregulation of growth factors leading to uncontrolled cellular proliferation, invasion and metastasis. Transforming growth factor (TGF)-β plays a crucial role in breast cancer because it has the potential to act as either a tumor suppressor or a pro-oncogenic chemokine. A cross-communication between the TGF-β signaling network and estrogens has been postulated, which is important for breast tumorigenesis. Here, we provide evidence that inhibition of TGF-β signaling is associated with a rapid estrogen-dependent nongenomic action. Moreover, we were able to demonstrate that estrogens disrupt the TGF-β signaling network as well as TGF-β functions in breast cancer cells via the G protein-coupled receptor 30 (GPR30). Silencing of GPR30 in MCF-7 cells completely reduced the ability of 17-β-estradiol (E2) to inhibit the TGF-β pathway. Likewise, in GPR30-deficient MDA-MB-231 breast cancer cells, E2 achieved the ability to suppress TGF-β signaling only after transfection with GPR30-encoding plasmids. It is most interesting that the antiestrogen fulvestrant (ICI 182,780), which possesses agonistic activity at the GPR30, also diminished TGF-β signaling. Further experiments attempted to characterize the molecular mechanism by which activated GPR30 inhibits the TGF-β pathway. Our results indicate that GPR30 induces the stimulation of the mitogen-activated protein kinases (MAPKs), which interferes with the activation of Smad proteins. Inhibition of MAPK activity prevented the ability of E2 from suppressing TGF-β signaling. These findings are of great clinical relevance, because down-regulation of TGF-β signaling is associated with the development of breast cancer resistance in response to antiestrogens. The American Society for Pharmacology and Experimental Therapeutics