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Silencing of syndecan-binding protein enhances the inhibitory effect of tamoxifen and increases cellular sensitivity to estrogen.

ABSTRACT: Objective:Tamoxifen is used as a complementary treatment for estrogen receptor (ER)-positive breast cancer (BCa), but many patients developed resistance. The aim of this study was to examine the role of syndecan-binding protein (SDCBP) silencing in ER-positive BCa cells. Methods:In MCF-7/T47D cells, the effects of SDCBP silence/overexpression on cell proliferation and estrogenic response were examined. Cell proliferation was examined using the MTT assay and cell cycle regulators were examined by Western blot. Estrogen response was examined from a luciferase activity and evaluation of transcript levels of pS2 and progesterone receptor (PR) upon estrogen administration. Samples of ER-positive BCa were stained with ER?, PR, and SDCBP antibodies, and their expression correlations were analyzed. Results:We found that SDCBP silencing inhibited the proliferation of ER-positive BCa cells and arrested a greater number of cells in the G1 phase of the cell cycle compared to tamoxifen alone, while SDCBP overexpression limited the anti-cancer effects of tamoxifen. SDCBP silencing and overexpression also enhanced and attenuated the estrogenic response, respectively. Expression of SDCBP was negatively correlated with PR, ER?, and the PR/ER? ratio in ER-positive BCa tissue samples. Conclusions:SDCBP may be involved in tamoxifen resistance in ER-positive BCa. Tamoxifen treatment combined with SDCBP silencing may provide a novel treatment for endocrine therapy-resistant BCa.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5842332 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Silencing of syndecan-binding protein enhances the inhibitory effect of tamoxifen and increases cellular sensitivity to estrogen.

Zhang Jun J Qian Xiaolong X Liu Fangfang F Guo Xiaojing X Gu Feng F Fu Li L

Cancer biology & medicine 20180201 1

<h4>Objective</h4>Tamoxifen is used as a complementary treatment for estrogen receptor (ER)-positive breast cancer (BCa), but many patients developed resistance. The aim of this study was to examine the role of syndecan-binding protein (SDCBP) silencing in ER-positive BCa cells.<h4>Methods</h4>In MCF-7/T47D cells, the effects of SDCBP silence/overexpression on cell proliferation and estrogenic response were examined. Cell proliferation was examined using the MTT assay and cell cycle regulators w ...[more]

PMID: 29545966

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Project description:BackgroundThe mechanisms of endocrine resistance are complex, and deregulation of several oncogenic signalling pathways has been proposed. We aimed to investigate the role of the EGFR and Src-mediated STAT3 signalling pathway in tamoxifen-resistant breast cancer cells.MethodsThe ER-positive luminal breast cancer cell lines, MCF-7 and T47D, were used. We have established an MCF-7-derived tamoxifen-resistant cell line (TamR) by long-term culture of MCF-7 cells with 4-hydroxytamoxifen. Cell viability was determined using an MTT assay, and protein expression levels were determined using western blot. Cell cycle and annexin V staining were analysed using flow cytometry.ResultsTamR cells showed decreased expression of estrogen receptor and increased expression of EGFR. TamR cells showed an acceleration of the G1 to S phase transition. The protein expression levels of phosphorylated Src, EGFR (Y845), and STAT3 was increased in TamR cells, while phosphorylated Akt was decreased. The expression of p-STAT3 was enhanced according to exposure time of tamoxifen in T47D cells, suggesting that activation of STAT3 can cause tamoxifen resistance in ER-positive breast cancer cells. Both dasatinib (Src inhibitor) and stattic (STAT3 inhibitor) inhibited cell proliferation and induced apoptosis in TamR cells. However, stattic showed a much stronger effect than dasatinib. Knockdown of STAT3 expression by siRNA had no effect on sensitivity to tamoxifen in MCF-7 cells, while that enhanced sensitivity to tamoxifen in TamR cells. There was not a significant synergistic effect of dasatinib and stattic on cell survival. TamR cells have low nuclear p21(Cip1) expression compared to MCF-7 cells and inhibition of STAT3 increased the expression of nuclear p21(Cip1) in TamR cells.ConclusionsThe EGFR and Src-mediated STAT3 signalling pathway is activated in TamR cells, and inhibition of STAT3 may be a potential target in tamoxifen-resistant breast cancer. An increase in nuclear p21(Cip1) may be a key step in STAT3 inhibitor-induced cell death in TamR cells.

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Silencing of syndecan-binding protein enhances the inhibitory effect of tamoxifen and increases cellular sensitivity to estrogen.

Publications

Silencing of syndecan-binding protein enhances the inhibitory effect of tamoxifen and increases cellular sensitivity to estrogen.

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