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

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
Breast Cancer Research and Treatment (Impact Factor: 4.47). 05/2009; 120(2):357-67. DOI: 10.1007/s10549-009-0393-2
Source: PubMed

ABSTRACT To investigate a presumed crosstalk between estrogen receptor alpha (ERalpha) 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 ERalpha, the transcription level of PAI-1 was upregulated, pointing to an attenuation of TGF-beta signaling by the presence of ERalpha. We verified these findings by a vice versa approach using a primary ER-negative cell model transiently overexpressing either ERalpha or ERbeta. We found that ERalpha, but not ERbeta, led to a strong inhibition of the TGF-beta1 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 ERalpha and suggest a ligand-independent crosstalk between ERalpha and TGF-beta signaling in breast cancer cells.

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    ABSTRACT: Multifunctional Y-box Binding Protein-1 (YB1) is correlated with a poor outcome in breast cancer. We found YB1 expression to be regulated by antiestrogens commonly used in the hormonal therapy of breast cancer and known as activators of Transforming Growth Factor-β (TGFβ). Thus, a putative influence of YB1 on TGFβ signaling should be investigated. The effect of YB1 on TGFβ signaling was monitored by expression analysis and reporter gene assays in breast cancer cells overexpressing YB1 and treated with antiestrogens. Antiestrogen-mediated inhibition of estrogen receptor-α led to a suppression of YB1 protein synthesis. On the other hand, YB1 was found to be an enhancer of TGFβ signaling. High levels of YB1 expression lead to a stimulation of TGFβ pathways, thereby counteracting antihormonal breast cancer therapy and representing a putative resistance mechanism.
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