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

Abstract

To investigate a presumed crosstalk between estrogen receptor a (ERa) and the TGF-b signaling pathway in breast cancer, we analyzed the TGF-b-induced expression of the plasminogen activator inhibitor 1 (PAI-1) gene in ER-positive MCF-7 cells. After siRNA-mediated knock-down of endogenous ERa, the transcription level of PAI-1 was upregulated, pointing to an attenuation of TGF-b signaling by the presence of ERa. We verified these findings by a vice versa approach using a primary ER-negative cell model transiently overexpressing either ERa or ERb. We found that ERa, but not ERb, led to a strong inhibition of the TGF-b1 signal, monitored by TGF-b reporter assays. This attenuation was completely independent of receptor stimulation by b-estradiol (E2) or inhibition by the pure antagonist ICI 182.780 (ICI). Our results indicate a permanent repression of PAI-1 by ERa and suggest a ligand-independent crosstalk between ERa and TGF-b signaling in breast cancer cells.

First trimester human placenta prevents breast cancer cell attachment to the matrix: The role of extracellular matrix

“…Placenta‐conditioned matrix reduced the ERα, which is a TGFβ pathway inhibitor . Moreover, the microarray results showed manipulation of the TGFβ pathway.…”

“…Indeed, the microarray data showed significantly decreased ESR1 and G Protein‐Coupled Estrogen Receptor (GPER) (FC = −1.45 and FC = −1.3, respectively) in the MCF‐7 cells that were cultured on the placenta‐conditioned ECM. There is crosstalk between the TGFβ and E2 pathways . These microarray results were the basis of our decision to further explore the E2, TGFβ, and integrin pathways in BCCL that were cultured on the placenta‐conditioned matrix and to analyze TGFβ and integrin pathway involvement in mediating the effects of ECM on the BCCL.…”

Fulvestrant regulates epidermal growth factor (EGF) family ligands to activate EGF receptor (EGFR) signaling in breast cancer cells

“…As mentioned before, one of the major actions for fulvestrant is rapidly down regulating ER. Stope et al have reported that ERα attenuates TGFβ signaling in breast cancer cells independent from agonistic and antagonistic ligands [38]. E-cadherin transcription has been reported been activated by unliganded ERα and suppressed by estrogen-activated ERα [39].…”

Transforming growth factor-β signaling in tumor initiation, progression and therapy in breast cancer: an update

“…Estrogen can disrupt the TGF-β signaling network in breast cancer cells via a G protein-coupled receptor 30 (GPR30)-mediated mitogen-activated protein kinase (MAPKs) pathway (Kleuser et al 2008). A ligandindependent cross-talk between ER-alpha and TGF-β is identified in breast cancer cells and may influence the development and/or progression of breast cancer (Band and Laiho 2011;Ren et al 2009;Stope et al 2010). Finally, cystatin C (CystC) is found to be a novel antagonist of TGF-β signaling in normal and malignant cells, reducing murine and human cell responsiveness to TGF-β (Tian and Schiemann 2009).…”