Dataset Information

TRPS1 Suppresses Breast Cancer Epithelial-mesenchymal Transition Program as a Negative Regulator of SUZ12.

ABSTRACT: Breast cancer (BC) is among the most common malignant diseases and metastasis is the handcuff of treatment. Cancer metastasis is a multistep process associated with the epithelial-mesenchymal transition (EMT) program. Several studies have demonstrated that transcriptional repressor GATA binding 1 (TRPS1) played important roles in development and progression of primary BC. In this study we sought to identify the mechanisms responsible for this function of TRPS1 in the continuum of the metastatic cascade. Here we described that TRPS1 was significantly associated with BC metastasis using public assessable datasets. Clinically, loss of TRPS1 expression in BC was related to higher histological grade. In vitro functional study and bioinformatics analysis revealed that TRPS1 inhibited cell migration and EMT in BC. Importantly, we identified SUZ12 as a novel target of TRPS1 related to EMT program. ChIP assay demonstrated TRPS1 directly inhibited SUZ12 transcription by binding to the SUZ12 promoter. Loss of TRPS1 resulted in increased SUZ12 binding and H3K27 tri-methylation at the CDH1 promoter and repression of E-cadherin. In all, our data indicated that TRPS1 maintained the expression of E-cadherin by inhibiting SUZ12, which might provide novel insight into how loss of TRPS1 contributed to BC progression.

SUBMITTER: Hu J

PROVIDER: S-EPMC5884189 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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TRPS1 Suppresses Breast Cancer Epithelial-mesenchymal Transition Program as a Negative Regulator of SUZ12.

Hu Jing J Su Peng P Jiao Meng M Bai Xinnuo X Qi Mei M Liu Hui H Wu Zhen Z Sun Jingtian J Zhou Gengyin G Han Bo B

Translational oncology 20180220 2

Breast cancer (BC) is among the most common malignant diseases and metastasis is the handcuff of treatment. Cancer metastasis is a multistep process associated with the epithelial-mesenchymal transition (EMT) program. Several studies have demonstrated that transcriptional repressor GATA binding 1 (TRPS1) played important roles in development and progression of primary BC. In this study we sought to identify the mechanisms responsible for this function of TRPS1 in the continuum of the metastatic ...[more]

PMID: 29471243

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Project description:BackgroundEribulin mesilate (eribulin), a non-taxane microtubule dynamics inhibitor, has shown trends towards greater overall survival (OS) compared with progression-free survival in late-stage metastatic breast cancer patients in the clinic. This finding suggests that eribulin may have additional, previously unrecognised antitumour mechanisms beyond its established antimitotic activity. To investigate this possibility, eribulin's effects on the balance between epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) in human breast cancer cells were investigated.MethodsTriple negative breast cancer (TNBC) cells, which are oestrogen receptor (ER-)/progesterone receptor (PR-)/human epithelial growth receptor 2 (HER2-) and have a mesenchymal phenotype, were treated with eribulin for 7 days, followed by measurement of EMT-related gene and protein expression changes in the surviving cells by quantitative real-time PCR (qPCR) and immunoblot, respectively. In addition, proliferation, migration, and invasion assays were also conducted in eribulin-treated cells. To investigate the effects of eribulin on TGF-β/Smad signalling, the phosphorylation status of Smad proteins was analysed. In vivo, the EMT/MET status of TNBC xenografts in mice treated with eribulin was examined by qPCR, immunoblot, and immunohistochemical analysis. Finally, an experimental lung metastasis model was utilised to gauge the metastatic activity of eribulin-treated TNBC in the in vivo setting.ResultsTreatment of TNBC cells with eribulin in vitro led to morphological changes consistent with transition from a mesenchymal to an epithelial phenotype. Expression analyses of EMT markers showed that eribulin treatment led to decreased expression of several mesenchymal marker genes, together with increased expression of several epithelial markers. In the TGF-β induced EMT model, eribulin treatment reversed EMT, coincident with inhibition of Smad2 and Smad3 phosphorylation. Consistent with these changes, TNBC cells treated with eribulin for 7 days showed decreased capacity for in vitro migration and invasiveness. In in vivo xenograft models, eribulin treatment reversed EMT and induced MET as assessed by qPCR, immunoblot, and immunohistochemical analyses of epithelial and mesenchymal marker proteins. Finally, surviving TNBC cells pretreated in vitro with eribulin for 7 days led to decreased numbers of lung metastasis when assessed in an in vivo experimental metastasis model.ConclusionsEribulin exerted significant effects on EMT/MET-related pathway components in human breast cancer cells in vitro and in vivo, consistent with a phenotypic switch from mesenchymal to epithelial states, and corresponding to observed decreases in migration and invasiveness in vitro as well as experimental metastasis in vivo. These preclinical findings may provide a plausible scientific basis for clinical observations of prolonged OS by suppression of further spread of metastasis in breast cancer patients treated with eribulin.

Dataset Information

TRPS1 Suppresses Breast Cancer Epithelial-mesenchymal Transition Program as a Negative Regulator of SUZ12.

Publications

TRPS1 Suppresses Breast Cancer Epithelial-mesenchymal Transition Program as a Negative Regulator of SUZ12.

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