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Human Primary Breast Cancer Stem Cells Are Characterized by Epithelial-Mesenchymal Plasticity.

ABSTRACT: Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, with only limited treatment options available. Recently, cancer stem cells (CSCs) have emerged as the potential drivers of tumor progression due to their ability to both self-renew and give rise to differentiated progeny. The CSC state has been linked to the process of epithelial-mesenchymal transition (EMT) and to the highly flexible state of epithelial-mesenchymal plasticity (EMP). We aimed to establish primary breast cancer stem cell (BCSC) cultures isolated from TNBC specimens. These cells grow as tumor spheres under anchorage-independent culture conditions in vitro and reliably form tumors in mice when transplanted in limiting dilutions in vivo. The BCSC xenograft tumors phenocopy the original patient tumor in architecture and gene expression. Analysis of an EMT-related marker profile revealed the concomitant expression of epithelial and mesenchymal markers suggesting an EMP state for BCSCs of TNBC. Furthermore, BCSCs were susceptible to stimulation with the EMT inducer TGF-?1, resulting in upregulation of mesenchymal genes and enhanced migratory abilities. Overall, primary BCSC cultures are a promising model close to the patient that can be used both in vitro and in vivo to address questions of BCSC biology and evaluate new treatment options for TNBC.

SUBMITTER: Strietz J

PROVIDER: S-EPMC7918351 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Human Primary Breast Cancer Stem Cells Are Characterized by Epithelial-Mesenchymal Plasticity.

Strietz Juliane J Stepputtis Stella S SS Follo Marie M Bronsert Peter P Stickeler Elmar E Maurer Jochen J

International journal of molecular sciences 20210211 4

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, with only limited treatment options available. Recently, cancer stem cells (CSCs) have emerged as the potential drivers of tumor progression due to their ability to both self-renew and give rise to differentiated progeny. The CSC state has been linked to the process of epithelial-mesenchymal transition (EMT) and to the highly flexible state of epithelial-mesenchymal plasticity (EMP). We aimed to establi ...[more]

PMID: 33670400

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Project description:The presence of circulating tumor cells (CTC) in breast cancer might be associated with stem cell-like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors. Furthermore, to be able to disseminate and metastasize, CTC must be able to perform epithelial-mesenchymal transition (EMT). We studied the expression of three EMT markers and the stem cell marker ALDH1 in CTC from 502 primary breast cancer patients. Data were correlated with the presence of disseminated tumor cells (DTC) in the bone marrow (BM) and with clinicopathological data of the patients.A total of 2 × 5 ml of blood was analyzed for CTC with the AdnaTest BreastCancer (AdnaGen AG) for the detection of EpCAM, MUC-1, HER2 and beta-Actin transcripts. The recovered c-DNA was additionally multiplex tested for three EMT markers [TWIST1, Akt2, phosphoinositide kinase-3 (PI3K?)] and separately for the tumor stem cell marker ALDH1. The identification of EMT markers was considered positive if at least one marker was detected in the sample. Two BM aspirates from all patients were analyzed for DTC by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3.Ninety-seven percent of 30 healthy donor samples investigated were negative for EMT and 95% for ALDH1 transcripts, respectively. CTC were detected in 97/502 (19%) patients. At least one of the EMT markers was expressed in 29% and ALDH1 was present in 14% of the samples, respectively. Interestingly, 5% of the ALDH1-positive and 18% of the EMT-positive patients were CTC-negative based on the cut-off level determined for CTC-positivity applying the AdnaTest BreastCancer. DTC in the BM were detected in 107/502 (21%) patients and no correlation was found between BM status and CTC positivity (P = 0.41). The presence of CTC, EMT and ALDH1 expression was not correlated to any of the prognostic clinical markers.Our data indicate that (1) a subset of primary breast cancer patients shows EMT and stem cell characteristics and (2) the currently used detection methods for CTC are not efficient to identify a subtype of CTC which underwent EMT. (3) The clinical relevance on prognosis and therapy response has to be further evaluated in a prospective trial.

Dataset Information

Human Primary Breast Cancer Stem Cells Are Characterized by Epithelial-Mesenchymal Plasticity.

Publications

Human Primary Breast Cancer Stem Cells Are Characterized by Epithelial-Mesenchymal Plasticity.

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