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)-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.
Footnotes
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This work was supported by grants of the Deutsche Forschungsgemeinschaft to B.K. (Kl 988 3-3 and Kl 988 4-2).
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ABBREVIATIONS: E2, 17-β-estradiol; BSA, bovine serum albumin; E2-BSA, 17-β-estradiol covalently linked to bovine serum albumin; EGF, epidermal growth factor; ER, estrogen receptor; ERE, estrogen response elements; ERK, extracellular-regulated kinase; FCS, fetal calf serum; GPR30, G protein coupled receptor 30; HRP, horseradish peroxidase; IGF, insulin-like growth factor; MAPK, mitogen-activated protein kinase; PBS, phosphate-buffered saline; PTX, pertussis toxin; siRNA, small interfering RNA; TGF, transforming growth factor; PCR, polymerase chain reaction; TBS, Tris-buffered saline; ICI 182,780, fulvestrant; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene.
- Received March 3, 2008.
- Accepted September 2, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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