Estrogen receptor α attenuates transforming growth factor-β signaling in breast cancer cells independent from agonistic and antagonistic ligands

To investigate a presumed crosstalk between estrogen receptor α (ERα) and the TGF-β signaling pathway in breast cancer, we analyzed the TGF-β-induced expression of the plasminogen activator inhibitor 1 (PAI-1) gene in ER-positive MCF-7 cells. After siRNA-mediated knock-down of endogenous ERα, the transcription level of PAI-1 was upregulated, pointing to an attenuation of TGF-β signaling by the presence of ERα. We verified these findings by a vice versa approach using a primary ER-negative cell model transiently overexpressing either ERα or ERβ. We found that ERα, but not ERβ, led to a strong inhibition of the TGF-β1 signal, monitored by TGF-β reporter assays. This attenuation was completely independent of receptor stimulation by β-estradiol (E2) or inhibition by the pure antagonist ICI 182.780 (ICI). Our results indicate a permanent repression of PAI-1 by ERα and suggest a ligand-independent crosstalk between ERα and TGF-β signaling in breast cancer cells.