17-Beta-estradiol inhibits transforming growth factor-beta signaling and function in breast cancer cells via activation of extracellular signal-regulated kinase through the G protein-coupled receptor 30.

Abstract

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)-beta 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-beta signaling network and estrogens has been postulated, which is important for breast tumorigenesis. Here, we provide evidence that inhibition of TGF-beta signaling is associated with a rapid estrogen-dependent nongenomic action. Moreover, we were able to demonstrate that estrogens disrupt the TGF-beta signaling network as well as TGF-beta 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-beta-estradiol (E2) to inhibit the TGF-beta pathway. Likewise, in GPR30-deficient MDA-MB-231 breast cancer cells, E2 achieved the ability to suppress TGF-beta 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-beta signaling. Further experiments attempted to characterize the molecular mechanism by which activated GPR30 inhibits the TGF-beta 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-beta signaling. These findings are of great clinical relevance, because down-regulation of TGF-beta signaling is associated with the development of breast cancer resistance in response to antiestrogens.

• Authors: Burkhard Kleuser, Daniela Malek, Ronald Gust, Heinz H Pertz, Henrik Potteck
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 74 Issue 6 Pg. 1533-43 (Dec 2008) ISSN: 1521-0111 [Electronic] United States
• PMID: 18768737 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Antagonists
• Estrogens
• GPER1 protein, human
• Receptors, Estrogen
• Receptors, G-Protein-Coupled
• Transforming Growth Factor beta
• Fulvestrant
• Estradiol
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Breast Neoplasms
• Cell Line, Tumor
• Enzyme Activation
• Estradiol (analogs & derivatives, pharmacology, physiology)
• Estrogen Antagonists (pharmacology)
• Estrogens (physiology)
• Female
• Fulvestrant
• Gene Silencing
• Humans
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Receptors, Estrogen
• Receptors, G-Protein-Coupled (agonists, genetics, physiology)
• Signal Transduction
• Transforming Growth Factor beta (physiology)