Article

Circulating Breast Tumor Cells Exhibit Dynamic Changes in Epithelial and Mesenchymal Composition

Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Science (Impact Factor: 33.61). 02/2013; 339(6119):580-584. DOI: 10.1126/science.1228522
Source: PubMed

ABSTRACT

Epithelial-mesenchymal transition (EMT) of adherent epithelial cells to a migratory mesenchymal state has been implicated
in tumor metastasis in preclinical models. To investigate its role in human cancer, we characterized EMT in circulating tumor
cells (CTCs) from breast cancer patients. Rare primary tumor cells simultaneously expressed mesenchymal and epithelial markers,
but mesenchymal cells were highly enriched in CTCs. Serial CTC monitoring in 11 patients suggested an association of mesenchymal
CTCs with disease progression. In an index patient, reversible shifts between these cell fates accompanied each cycle of response
to therapy and disease progression. Mesenchymal CTCs occurred as both single cells and multicellular clusters, expressing
known EMT regulators, including transforming growth factor (TGF)–β pathway components and the FOXC1 transcription factor.
These data support a role for EMT in the blood-borne dissemination of human breast cancer.

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Available from: Shannon L Stott, Apr 15, 2014
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    • "Hence, the transition phase cannot easily be parsed and evaluated at a specific time or growth stage. Recently Yu et al. established a dual-colorimetric RNA in situ hybridization (ISH) assay to characterize EMT in circulating tumor cells (CTCs) from breast cancer patients[30]. They examined seven pooled epithelial transcripts (Keratins 5, 7, 8, 18, and 19; EpCAM (epithelial cellular adhesion molecule) and E-cadherin) and three mesenchymal transcripts (fibronectin, N-cadherin, and SERPINE1/PAI1 (serpin peptidase inhibitor, clade E)) in 11 human breast cancer specimens. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer is the most common cancer in women and distant site metastasis is the main cause of death in breast cancer patients. There is increasing evidence supporting the role of epithelial-mesenchymal transition (EMT) in tumor cell progression, invasion, and metastasis. During the process of EMT, epithelial cancer cells acquire molecular alternations that facilitate the loss of epithelial features and gain of mesenchymal phenotype. Such transformation promotes cancer cell migration and invasion. Moreover, emerging evidence suggests that EMT is associated with the increased enrichment of cancer stem-like cells (CSCs) and these CSCs display mesenchymal characteristics that are resistant to chemotherapy and target therapy. However, the clinical relevance of EMT in human cancer is still under debate. This review will provide an overview of current evidence of EMT from studies using clinical human breast cancer tissues and its associated challenges.
    Preview · Article · Jan 2016 · Journal of Clinical Medicine
    • "Comparative genome hybridization (array cGH) can detect chromosomal aberrations in CTCs (Neves et al., 2014;Polzer et al., 2014); copy number variations can also be detected using qPCR. Characterization of CTCs on single cell level is also possible on transcriptome level, which was shown using RT-PCR (Powell et al., 2012), RNA sequencing (Cann et al., 2012) or RNA in situhybridization (Yu et al., 2013). Cultivation of CTCs is another approach to individually analyze drug susceptibility (Yu et al., 2014) and to predict therapy response (Khoo et al., 2015). "
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    ABSTRACT: The phenomenon of tumor cell dissemination through the blood stream has been known since the 19th century. Circulating tumor cells (CTCs) may be detected in peripheral blood of patients with breast cancer and may serve as a surrogate marker for minimal residual disease. Prognostic relevance of CTCs has already been demonstrated in early and metastatic breast cancer and commercially available detection systems are currently employed in various clinical trials. Since peripheral blood is an easily accessible compartment, serial reevaluation of CTCs is possible and may contribute to better therapy monitoring. Another potential of CTCs lies in the characterization of tumor cells. Expression profiles may differ between CTCs and primary tumor, which may result in different responses to treatment. Assessment of molecular features of CTCs may be an important step for the optimization of adjuvant and metastatic systemic therapy.
    No preview · Article · Nov 2015 · Critical reviews in oncology/hematology
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    • "It has been reported that transformation from a luminal primary to a basal-like recurrence is more likely than the opposite phenomena (Castaneda et al., 2012). Recent studies showed that FOXC1 is associated with mesenchymal circulating tumor cells from both ER + and ER – breast cancer and may induce EMT in ER + breast cancer cells (Yu et al., 2013). Thus, we explored the effect of FOXC1 on CSC properties in two ER + cell lines, MCF7 and T47D, which harbor undetectable FOXC1 levels (Figure S1A). "
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    ABSTRACT: The mesoderm- and epithelial-mesenchymal transition-associated transcription factor FOXC1 is specifically overexpressed in basal-like breast cancer (BLBC), but its biochemical function is not understood. Here we demonstrate that FOXC1 controls cancer stem cell (CSC) properties enriched in BLBC cells via activation of Smoothened (SMO)-independent Hedgehog (Hh) signaling. This non-canonical activation of Hh is specifically mediated by Gli2. We further show that the N-terminal domain of FOXC1 (aa 1-68) binds directly to an internal region (aa 898-1168) of Gli2, enhancing the DNA-binding and transcription-activating capacity of Gli2. FOXC1 expression correlates with that of Gli2 and its targets in human breast cancers. Moreover, FOXC1 overexpression reduces sensitivity to anti-Hedgehog (Hh) inhibitors in BLBC cells and xenograft tumors. Together, these findings reveal FOXC1-mediated non-canonical Hh signaling that determines the BLBC stem-like phenotype and anti-Hh sensitivity, supporting inhibition of FOXC1 pathways as potential approaches for improving BLBC treatment.
    Full-text · Article · Nov 2015 · Cell Reports
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