Estrogen Inhibits Transforming Growth Factor β Signaling by Promoting Smad2/3 Degradation

Abstract

Estrogen is a growth factor that stimulates cell proliferation. The effects of estrogen are mediated through the estrogen receptors, ER␣ and ER␤, which function as ligand-induced transcription factors and belong to the nuclear receptor superfamily. On the other hand, TGF-␤ acts as a cell growth inhibitor, and its signaling is transduced by Smads. Although a number of studies have been made on the cross-talk between estrogen/ER␣ and TGF-␤/Smad signaling, whose molecular mechanisms remain to be determined. Here, we show that ER␣ inhibits TGF-␤ signaling by decreasing Smad protein levels. ER␣-mediated reductions in Smad levels did not require the DNA binding ability of ER␣, implying that ER␣ opposes the effects of TGF-␤ via a novel non-genomic mechanism. Our analysis revealed that ER␣ formed a protein complex with Smad and the ubiquitin ligase Smurf, and enhanced Smad ubiquitination and subsequent degradation in an estrogen-dependent manner. Our observations provide new insight into the molecular mechanisms governing the non-genomic functions of ER␣.

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Estrogen treatment is shown to reduce the phosphorylation of Smad2 and Smad3 [231]. when ERα is in a ligand activated form, it physically interacts with Smad2 and Smad3 [231].…”

“…Estrogen receptor activation is shown to inhibit transcriptional activity of TGF-β as determined by reporter assays by up to 60 % [231]. Furthermore, microarray analysis of MCF-7 breast cancer cells revealed that TGF-β treatment more than doubles the expression of 956 genes whereas estrogen treatment reduces the expression of 683 genes [231]. ERα is a major modifier of TGF-β signaling cascade, and activin and ER signaling suppress one another [232].…”

“…when ERα is in a ligand activated form, it physically interacts with Smad2 and Smad3 [231]. The interaction recruits Smurf1, the ubiquitin ligase, to the complex to ubiquitylate Smad2/3.…”

“…The interaction recruits Smurf1, the ubiquitin ligase, to the complex to ubiquitylate Smad2/3. The ubiquitin-proteasome pathway leads to Smad degradation [231]. However, many conflicting reports on the ability of ERα to reduce Smad2/3 levels exist [233].…”

“…Therefore ERα appears to regulate TGF-β signaling through a non-genomic mechanism. ERβ may also inhibit TGF-β signaling by enhancing Smad2/3 degradation in an estrogen-dependent manner [231]. Consequently, activation of ERα signaling leads to the reduction of both TGF-β induced migration and invasion of breast cancer cells [231].…”