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Superior breast cancer metastasis risk stratification using an epithelial-mesenchymal-amoeboid transition gene signature.

ABSTRACT: BACKGROUND:Cancer cells are known to display varying degrees of metastatic propensity, but the molecular basis underlying such heterogeneity remains unclear. Our aims in this study were to (i) elucidate prognostic subtypes in primary tumors based on an epithelial-to-mesenchymal-to-amoeboid transition (EMAT) continuum that captures the heterogeneity of metastatic propensity and (ii) to more comprehensively define biologically informed subtypes predictive of breast cancer metastasis and survival in lymph node-negative (LNN) patients. METHODS:We constructed a novel metastasis biology-based gene signature (EMAT) derived exclusively from cancer cells induced to undergo either epithelial-to-mesenchymal transition (EMT) or mesenchymal-to-amoeboid transition (MAT) to gauge their metastatic potential. Genome-wide gene expression data obtained from 913 primary tumors of lymph node-negative breast cancer (LNNBC) patients were analyzed. EMAT gene signature-based prognostic stratification of patients was performed to identify biologically relevant subtypes associated with distinct metastatic propensity. RESULTS:Delineated EMAT subtypes display a biologic range from less stem-like to more stem-like cell states and from less invasive to more invasive modes of cancer progression. Consideration of EMAT subtypes in combination with standard clinical parameters significantly improved survival prediction. EMAT subtypes outperformed prognosis accuracy of receptor or PAM50-based BC intrinsic subtypes even after adjusting for treatment variables in 3 independent, LNNBC cohorts including a treatment-naïve patient cohort. CONCLUSIONS:EMAT classification is a biologically informed method that provides prognostic information beyond that which can be provided by traditional cancer staging or PAM50 molecular subtype status and may improve metastasis risk assessment in early stage, LNNBC patients, who may otherwise be perceived to be at low metastasis risk.

SUBMITTER: Emad A

PROVIDER: S-EPMC7341640 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Superior breast cancer metastasis risk stratification using an epithelial-mesenchymal-amoeboid transition gene signature.

Emad Amin A Ray Tania T Jensen Tor W TW Parat Meera M Natrajan Rachael R Sinha Saurabh S Ray Partha S PS

Breast cancer research : BCR 20200708 1

<h4>Background</h4>Cancer cells are known to display varying degrees of metastatic propensity, but the molecular basis underlying such heterogeneity remains unclear. Our aims in this study were to (i) elucidate prognostic subtypes in primary tumors based on an epithelial-to-mesenchymal-to-amoeboid transition (EMAT) continuum that captures the heterogeneity of metastatic propensity and (ii) to more comprehensively define biologically informed subtypes predictive of breast cancer metastasis and su ...[more]

PMID: 32641077

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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

Superior breast cancer metastasis risk stratification using an epithelial-mesenchymal-amoeboid transition gene signature.

Publications

Superior breast cancer metastasis risk stratification using an epithelial-mesenchymal-amoeboid transition gene signature.

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