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Trefoil factor 3 promotes metastatic seeding and predicts poor survival outcome of patients with mammary carcinoma.

ABSTRACT: Recurrence or early metastasis remains the predominant cause of mortality in patients with estrogen receptor positive (ER+) mammary carcinoma (MC). However, the molecular mechanisms underlying the initial progression of ER+?MC to metastasis remains poorly understood. Trefoil factor 3 (TFF3) is an estrogen-responsive oncogene in MC. Herein, we provide evidence for a functional role of TFF3 in metastatic progression of ER+?MC.The association of TFF3 expression with clinicopathological parameters and survival outcome in a cohort of MC patients was assessed by immunohistochemistry. The expression of TFF3 in MCF7 and T47D cells was modulated by forced expression or siRNA-mediated depletion of TFF3. mRNA and protein levels were determined using qPCR and western blot. The functional effect of modulation of TFF3 expression in MC cells was determined in vitro and in vivo. Mechanistic analyses were performed using reporter constructs, modulation of signal transducer and activator of transcription 3 (STAT3) expression, and pharmacological inhibitors against c-SRC and STAT3 activity.TFF3 protein expression was positively associated with larger tumour size, lymph node metastasis, higher stage, and poor survival outcome. Forced expression of TFF3 in ER+?MC cells stimulated colony scattering, cell adhesion to a Collagen I-coated matrix, colony formation on a Collagen I- or Matrigel-coated matrix, endothelial cell adhesion, and transmigration through an endothelial cell barrier. In vivo, forced expression of TFF3 in MCF7 cells stimulated the formation of metastatic nodules in animal lungs. TFF3 regulation of the mRNA levels of epithelial, mesenchymal, and metastatic-related genes in ER+?MC cells were consistent with the altered cell behaviour. Forced expression of TFF3 in ER+?MC cells stimulated phosphorylation of c-SRC that subsequently increased STAT3 activity, which lead to the downregulation of E-cadherin. siRNA-mediated depletion of TFF3 reduced the invasiveness of ER+?MC cells.TFF3 expression predicts metastasis and poor survival outcome of patients with MC and functionally stimulates cellular invasion and metastasis of ER+?MC cells. Adjuvant functional inhibition of TFF3 may therefore be considered to ameliorate outcome of ER+?MC patients.

SUBMITTER: Pandey V

PROVIDER: S-EPMC4303111 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Trefoil factor 3 promotes metastatic seeding and predicts poor survival outcome of patients with mammary carcinoma.

Pandey Vijay V Wu Zheng-Sheng ZS Zhang Min M Li Rui R Zhang Jian J Zhu Tao T Lobie Peter E PE

Breast cancer research : BCR 20140930 5

<h4>Introduction</h4>Recurrence or early metastasis remains the predominant cause of mortality in patients with estrogen receptor positive (ER+) mammary carcinoma (MC). However, the molecular mechanisms underlying the initial progression of ER+ MC to metastasis remains poorly understood. Trefoil factor 3 (TFF3) is an estrogen-responsive oncogene in MC. Herein, we provide evidence for a functional role of TFF3 in metastatic progression of ER+ MC.<h4>Methods</h4>The association of TFF3 expression ...[more]

PMID: 25266665

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Project description:IntroductionARTEMIN (ARTN) is an estrogen regulated growth factor, the expression of which promotes resistance to antiestrogen therapies and predicts poorer survival outcome of patients with estrogen receptor (ER) positive mammary carcinoma (ER+MC) treated with tamoxifen. ARTN is also expressed in ER negative mammary carcinoma (ER-MC). Herein, we determined the role of ARTN in ER-MC and defined the mechanism of action producing poor patient prognosis.MethodsWe modulated the expression of ARTN in two ER- (mesenchymal/claudin-low) mammary carcinoma cell lines (BT549 and MDA-MB-231) by forced expression or small interfering RNA (siRNA) mediated depletion. The effects of modulation of ARTN expression were examined by various in vitro measures of oncogenicity, including the expression of TWIST1 messenger RNA (mRNA) and protein. In vitro results were correlated to xenograft studies in immunodeficient mice. Co-expression of ARTN and TWIST1 and their association to poor survival outcome were examined in a cohort of patients with ER-MC. Pathway analysis was performed by pharmacological inhibition of phosphorylation of AKT (pAKT-Ser 473) or modulation of TWIST1 expression.ResultsARTN expression resulted in ER-MC cells with enhanced mesenchymal characteristics, including increased invasion and a gene expression profile consistent with enhanced mesenchymal phenotype. ARTN stimulated ER-MC cell anchorage independent and 3D matrigel growth, endothelial cell adhesion and transmigration of ER-MC cells through an endothelial cell barrier. Forced expression of ARTN produced a larger, locally invasive tumour mass with tumour emboli that produced distant metastasis. ARTN regulated TWIST1 expression in ER-MC cells and ARTN expression was significantly correlated to TWIST1 expression in a panel of mammary carcinoma cell lines and in a cohort of patients with ER-MC. Low expression of both ARTN and TWIST1 predicted 100% relapse free and overall survival in patients with ER-MC, whereas high expression of both ARTN and TWIST1 was associated with a poor survival outcome. ARTN stimulated an increase in TWIST1 expression via increased AKT activity. siRNA mediated depletion of TWIST1 abrogated ARTN stimulated cellular behaviour associated with metastasis, and forced expression of TWIST1 abrogated the functional effects of ARTN depletion.ConclusionsARTN and TWIST1 synergize to produce a worse outcome in ER-MC and combined inhibition of ARTN and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) may therefore provide a novel therapeutic strategy in this subtype of mammary carcinoma.

Project description:BackgroundAngiopoietin growth factors (Angs) regulate angiogenesis and lymphangiogenesis by binding to the endothelial Tie2 receptor. Ang2 expression is elevated in tissue hypoxia and inflammation, which also induce cleavage of the extracellular domain of the orphan Tie1 receptor. Here we have examined if the concentrations of Ang2 and the soluble extracellular domain of Tie1 in patient plasma are associated with the prognosis of patients with metastatic breast cancer.MethodsPlasma Tie1 and Ang2 levels were measured in metastatic breast cancer patients treated in a phase II trial with a taxane-bevacizumab combination chemotherapy in the first-line treatment setting. They were analyzed before treatment, after 6 weeks and 6 months of treatment, and at the final study visit. Using the median concentrations as cutoffs, Tie1 and Ang2 data were dichotomized into low and high concentration groups. Additionally, we analyzed Tie1 concentrations in plasma from 10 healthy women participating in a breast cancer primary prevention study.ResultsPlasma samples were available from 58 (89%) of the 65 patients treated in the trial. The baseline Tie1 levels of the healthy controls were significantly lower than those of the metastatic patients (p < 0.001). The overall survival of the patients with a high baseline Tie1 level was significantly shorter (multivariate HR 3.07, 95% CI 1.39-6.79, p = 0.005). Additionally, the progression-free survival was shorter for patients with a high baseline Tie1 level (multivariate HR 3.78, 95% CI 1.57-9.09, p = 0.003). In contrast, the baseline Ang2 levels had no prognostic impact in a multivariate Cox proportional hazard regression analysis. The combined analysis of baseline Tie1 and Ang2 levels revealed that patients with both high Tie1 and high Ang2 baseline levels had a significantly shorter overall survival than the patients with low baseline levels of both markers (multivariate HR for overall survival 4.32, 95% CI 1.44-12.94, p = 0.009).ConclusionsThis is the first study to demonstrate the prognostic value of baseline Tie1 plasma concentration in patients with metastatic breast cancer. Combined with the results of the Ang2 analyses, the patients with both high Tie1 and Ang2 levels before treatment had the poorest survival.Trial registrationClinicaltrials.gov: NCT00979641, registration date 19-DEC-2008. The regional Ethics Committee: R08142M, registration date 18-NOV-2008.

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Trefoil factor 3 promotes metastatic seeding and predicts poor survival outcome of patients with mammary carcinoma.

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Trefoil factor 3 promotes metastatic seeding and predicts poor survival outcome of patients with mammary carcinoma.

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