Trefoil Factor 3 Is Oncogenic and Mediates Anti-Estrogen Resistance in Human Mammary Carcinoma

Kannan, Nagarajan; Kang, Jian; Kong, Xiangjun; Tang, Jun; Perry, Jo K.; Mohankumar, Kumarasamypet M.; Miller, Lance D.; Liu, Edison T.; Mertani, Hichem C.; Zhu, Tao; Grandison, Prudence M.; Liu, Dong-Xu; Lobie, Peter E.

doi:10.1593/neo.10916

Cited by 61 publications

(132 citation statements)

References 66 publications

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“…We have previously shown that TFF3 activates cell survival signaling pathways which contribute to anti-estrogen resistance in mammary carcinoma [16]. TFF3-enhanced cell survival and tamoxifen resistance have both been suggested to be dependent on BCL-2 [16]. Consistently in this study, we identified BCL-2 as an important downstream mediator of cell survival and doxorubicin resistance in HCC.…”

Section: Discussionsupporting

confidence: 89%

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Trefoil factor 3 mediation of oncogenicity and chemoresistance in hepatocellular carcinoma is AKT-BCL-2 dependent

et al. 2017

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The efficacious treatment of hepatocellular carcinoma (HCC) remains a challenge, partially being attributed to intrinsic chemoresistance. Previous reports have observed increased TFF3 expression in HCC. Herein, we investigated the functional role of TFF3 in progression of HCC, and in both intrinsic and acquired chemoresistance. TFF3 expression was observed to be upregulated in HCC and associated with poor clinicopathological features and worse patient survival outcome. Functionally, forced expression of TFF3 in HCC cell lines increased cell proliferation, cell survival, anchorage-independent and 3D matrigel growth, cell invasion and migration, and in vivo tumor growth. In contrast, depleted expression of TFF3 decreased the oncogenicity of HCC cells as indicated by the above parameters. Furthermore, forced expression of TFF3 decreased doxorubicin sensitivity of HCC cells, which was attributed to increased doxorubicin efflux and cancer stem cell-like behavior of Hep3B cells. In contrast, depletion of TFF3 increased doxorubicin sensitivity and decreased cancer stem cell-like behavior of Hep3B cells. Correspondingly, TFF3 expression was markedly increased in Hep3B cells with acquired doxorubicin resistance, while the depletion of TFF3 resulted in re-sensitization of the Hep3B cells to doxorubicin. The increased doxorubicin efflux and enhanced cancer stem cell-like behavior of the doxorubicin-resistant Hep3B cells was observed to be dependent on TFF3 expression. In addition, we determined that TFF3-stimulated oncogenicity and chemoresistance in HCC cells was mediated by AKT-dependent expression of BCL-2. Hence, therapeutic inhibition of TFF3 should be considered to hinder HCC progression and overcome intrinsic and acquired chemoresistance in HCC.

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Section: Discussionsupporting

confidence: 89%

“…Real-time quantitative PCR (qPCR) was also performed to analyse mRNA expression levels [16]. Primer used for RT-PCR and qPCR are as previously described [81].…”

Section: Methodsmentioning

confidence: 99%

Trefoil factor 3 mediation of oncogenicity and chemoresistance in hepatocellular carcinoma is AKT-BCL-2 dependent

et al. 2017

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“…Therefore, detecting or preventing cervical cancers with progressions in early is critical, which could help to prolong patient survival. As we know TFF3 is a soluble peptide containing trefoil domain and C-terminal dimerization domain which is not only a novel prognostic marker but also a therapeutic target in various cancers, such as mammary carcinoma, gastric cancer and prostate carcinoma [5–8]. Upregulation of TFF3 after rectal cancer chemo-radiotherapy is an adverse prognostic factor [9].…”

Section: Introductionmentioning

confidence: 99%

“…TFF3, behaved as an oncogene, promotes proliferation and invasion, improves survival, and increases oncogenicity in cancer cells, such as mammary carcinoma, gastric cancer and prostate carcinoma [5, 11]. TFF3 promoted epithelial tumorigenesis by inducing aberrant proliferation and inhibiting apoptosis [7].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of trefoil factor 3 (TFF3) contributes to the malignant progression in cervical cancer cells

Zhang

Chen

et al. 2017

Cancer Cell Int

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BackgroundThere remains a great need for effective therapies for cervical cancers, the majority of which are aggressive leaving patients with poor prognosis.Methods and resultsHere, we identify a novel candidate therapeutic target, trefoil factor 3 (TFF3) which overexpressed in cervical cancer cells and was associated with reduced postoperative survival. Functional studies demonstrated that TFF3 overexpression promoted the proliferation and invasion of cervical cancer cells, and inhibited the apoptosis by inducing the mRNA changes in SiHa and Hela cell lines. Conversely, TFF3 silencing disrupted the proliferation and invasion of cervical cancer cells, and induced the apoptosis via Click-iT EdU test, flow cytometry analysis and two-dimensional Matrigel Transwell analysis. Western blot analysis showed that overexpression of TFF3 repressed E-cadherin (CDH1) expression to promote the invasion of cervical cancer cells. Furthermore, down-regulated CDH1 via overexpression of TFF3 was significantly up-regulated by virtue of inhibitor of p-STAT3.ConclusionsThese results suggested that TFF3 stimulated the invasion of cervical cancer cells probably by activating the STAT3/CDH1 signaling pathway. Furthermore, overexpression of TFF3 decreased the sensitivity of cervical cancer cells to etoposide by increasing P-glycoprotein (P-gp) functional activity. Overall, our work provides a preclinical proof that TFF3 not only contributes to the malignant progression of cervical cancers and but also is a potential therapeutic target.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-016-0379-1) contains supplementary material, which is available to authorized users.

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“…The trefoil factor family is characterized by a 40 amino acid motif and interestingly another member of this family, TFF3, is found in the feature list of the combined model (Supplemental Table 1). TFF3 expression is positively correlated with the status of the estrogen receptor in adenocarcinoma [25] and TFF3 is furthermore associated with breast cancer invasion and metastasis [26], as well as treatment resistance [27].…”

Section: Most Important Featuresmentioning

confidence: 99%

Classification of Breast Cancer Subtypes by combining Gene Expression and DNA Methylation Data

List

Hauschild

Tan

et al. 2014

Journal of Integrative Bioinformatics

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SummarySelecting the most promising treatment strategy for breast cancer crucially depends on determining the correct subtype. In recent years, gene expression profiling has been investigated as an alternative to histochemical methods. Since databases like TCGA provide easy and unrestricted access to gene expression data for hundreds of patients, the challenge is to extract a minimal optimal set of genes with good prognostic properties from a large bulk of genes making a moderate contribution to classification. Several studies have successfully applied machine learning algorithms to solve this so-called gene selection problem. However, more diverse data from other OMICS technologies are available, including methylation. We hypothesize that combining methylation and gene expression data could already lead to a largely improved classification model, since the resulting model will reflect differences not only on the transcriptomic, but also on an epigenetic level. We compared so-called random forest derived classification models based on gene expression and methylation data alone, to a model based on the combined features and to a model based on the gold standard PAM50. We obtained bootstrap errors of 10-20% and classification error of 1-50%, depending on breast cancer subtype and model. The gene expression model was clearly superior to the methylation model, which was also reflected in the combined model, which mainly selected features from gene expression data. However, the methylation model was able to identify unique features not considered as relevant by the gene expression model, which might provide deeper insights into breast cancer subtype differentiation on an epigenetic level.

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Trefoil Factor 3 Is Oncogenic and Mediates Anti-Estrogen Resistance in Human Mammary Carcinoma

Cited by 61 publications

References 66 publications

Trefoil factor 3 mediation of oncogenicity and chemoresistance in hepatocellular carcinoma is AKT-BCL-2 dependent

Trefoil factor 3 mediation of oncogenicity and chemoresistance in hepatocellular carcinoma is AKT-BCL-2 dependent

Overexpression of trefoil factor 3 (TFF3) contributes to the malignant progression in cervical cancer cells

Classification of Breast Cancer Subtypes by combining Gene Expression and DNA Methylation Data

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