Dual effects of TGF-β on ERα-mediated estrogenic transcriptional activity in breast cancer

Abstract

BackgroundTGF-β resistance often develops in breast cancer cells that in turn overproduce this cytokine to create a local immunosuppressive environment that fosters tumor growth and exacerbates the invasive and metastatic behavior of the tumor cells themselves. Smads-mediated cross-talk with the estrogen receptor has been implied to play an important role in development and/or progression of breast cancer. We investigated how TGF-β regulates ERα-induced gene transcription and potential mechanisms of frequent TGF-β resistance in breast cancer.MethodsEffect of TGF-β on ERα-mediated gene transcription was investigated in breast cancer cell lines using transient transfection, real-time PCR, sequential DNA precipitation, and small interfering RNA assays. The expression of Smads on both human breast cancer cell lines and ERα-positive human breast cancer tissue was evaluated by immunofluorescence and immunohistochemical assays.ResultsA complex of Smad3/4 mediates TGF-β inhibition of ERα-mediated estrogenic activity of gene transcription in breast cancer cells, and Smad4 is essential and sufficient for such repression. Either overexpression of Smad3 or inhibition of Smad4 leads to the "switch" of TGF-β from a repressor to an activator. Down-regulation and abnormal cellular distribution of Smad4 were associated with some ERα-positive infiltrating human breast carcinoma. There appears a dynamic change of Smad4 expression from benign breast ductal tissue to infiltrating ductal carcinoma.ConclusionThese results suggest that aberrant expression of Smad4 or disruption of Smad4 activity lead to the loss of TGF-β suppression of ERα transactivity in breast cancer cells.

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…In contrast to Smad2/3, the interaction with ERα does not lead to Smad4 degradation [234]. Overexpression of Smad3 or inhibition of Smad4 leads to a change of role of TGF-β from a repressor to an activator of the ERα signaling cascade [235]. On the other hand, Smad4 can induce apoptosis in an ERα-dependent manner in ERα-positive but not in ERα-negative breast cancer cells.…”

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

“…Smad3-dependent transcription is inhibited by ER␣ through binding to Smad3, and the inhibition is abrogated by the expression of AP-1 transcription factors (33,34). A complex of Smad3/4 mediates the inhibition of ER␣-mediated estrogenic activity of gene transcription in breast cancer cells (35). In addition, ER␣ interacts with Smad1, which is a downstream signal transducer of BMP signaling, to inhibit BMP-induced transcription (36,37).…”

TGF-B signaling pathway, ER-a and the heterogeneity of breast cancer risk among hispanic and non-hispanic white women.

“…R-SMAD3 has been found to be a co-activator of ERα changing the role of TGF-β. In the absence of Co-SMAD4, TGF-β can regulate ERα transcription through a R-SMAD3-mediated process and enhance the estrogen-ERα cell proliferation [131]. In fact, Araki and colleagues found that 65% of late stage breast cancers are characterized by activated R-SMAD3 and HDM2, a negative regulator of the tumor suppressor p53 [134].…”

“…Several studies have provided evidence that receptor regulated SMADs (R-SMAD2, R-SMAD3) and common mediator (Co-SMAD4) comes into direct physical contact with ERα [129][130][131][132]. Co-SMAD4 is found to be a mediator of crosstalk between TGF-β and ERα where it acts as a co-repressor of the transcription of ERα, inhibiting tumor growth.…”

“…Interestingly, Co-SMAD4 has been found to induce apoptosis in ERα+ but not ERα-cells [133]. In the absence of Co-SMAD4, ERα-estrogen cell proliferation is enhanced [131]. Estrogen will act acting directly on the TGF-β signaling pathway to block the phosphorylation of R-SMAD 2/3 complex via ubiquitinproteasome pathway [130].…”