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

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