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Epithelial Mesenchymal Transition Traits in Human Breast Cancer Cell Lines Parallel the CD44hi/CD24lo/- Stem Cell Phenotype in Human Breast Cancer

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Abstract

We review here the recently emerging relationship between epithelial-mesenchymal transition (EMT) and breast cancer stem cells (BCSC), and provide analyses of published data on human breast cancer cell lines, supporting their utility as a model for the EMT/BCSC state. Genome-wide transcriptional profiling of these cell lines has confirmed the existence of a subgroup with mesenchymal tendencies and enhanced invasive properties (‘Basal B’/Mesenchymal), distinct from subgroups with either predominantly luminal (‘Luminal’) or mixed basal/luminal (‘Basal A’) features (Neve et al. Cancer Cell, 2006). A literature-derived EMT gene signature has shown specific enrichment within the Basal B subgroup of cell lines, consistent with their over-expression of various EMT transcriptional drivers. Basal B cell lines are found to resemble BCSC, being CD44highCD24low. Moreover, gene products that distinguish Basal B from Basal A and Luminal cell lines (Basal B Discriminators) showed close concordance with those that define BCSC isolated from clinical material, as reported by Shipitsin et al. (Cancer Cell, 2007). CD24 mRNA levels varied across Basal B cell lines, correlating with other Basal B Discriminators. Many gene products correlating with CD24 status in Basal B cell lines were also differentially expressed in isolated BCSC. These findings confirm and extend the importance of the cellular product of the EMT with Basal B cell lines, and illustrate the value of analysing these cell lines for new leads that may improve breast cancer outcomes. Gene products specific to Basal B cell lines may serve as tools for the detection, quantification, and analysis of BCSC/EMT attributes.

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Abbreviations

ALDH1:

Aldehyde dehydrogenase 1 family, member A1

BCSC:

Breast cancer stem cells

BRCA1:

Breast cancer 1, early onset

C/EBP β-2:

CCAAT/enhancer binding protein (C/EBP), beta

CDH1:

E-cadherin

COX-2:

Cyclooxygenase-2

CTC:

Circulating tumor cells

DDR1:

Discoidin domain receptor tyrosine kinase 1

DTC:

Disseminated tumor cells

EGF:

Epidermal growth factor

EMT:

Epithelial-to-mesenchymal transition

EMT-SIG:

EMT-signature

EMP3:

Epithelial membrane protein 3

ER:

Estrogen receptor

EndMT:

Endothelial-to-mesenchymal transition

FAK:

Focal adhesion kinase

FOSL:

Fos-like antigen

GAS6:

Growth arrest-specific 6

HEEBO:

Human exonic evidence based oligonucleotide array

HOXB7:

Homeobox B7

HMLE:

Human mammary epithelial cells

HR:

Hazard recurrence

MaSC:

Mammary stem cells

MEC:

Mammary epithelial cells

MET:

Mesenchymal-to-epithelial transition

mRNA:

Messenger RNA

NFkB:

Nuclear factor kappa B

PGI/AMF:

Phosphoglucose isomerise/autocrine motility factor

PROCR:

Protein C receptor, endothelial (EPCR)

shRNA:

Short hairpin ribonucleic acid

Src:

Src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)

TGF-beta:

Transforming growth factor-beta

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Acknowledgements

The research effort associated with this article was funded in part by the U.S. Army Medical Research and Materiel Command (BC0213201 and BC084667), the Victorian Breast Cancer Research Consortium, The Cancer Council Victoria (#509295) and the National Breast Cancer Foundation (Australia). TB and EWT were supported in part by the Victorian Breast Cancer Research Consortium. HH is supported by a fellowship from the National Breast Cancer Foundation, Australia. EW is the recipient of an AUS Aid Scholarship. Parts of this work were also supported by the U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research (Contract DE-AC03-76SF00098) and the California Breast Cancer Research Program (CBCRP) grant # 7FB-0027. SAM lab is supported by V foundations V Scholar award and M. D. Anderson Research Trust Fellow award. RAW is supported in part by the Breast Cancer Research Foundation. The authors are grateful to Dr. Kornelia Polyak for providing prepublication data from the Shipitsin et al. study (2007) for comparative analysis.

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Authors and Affiliations

  1. Invasion and Metastasis Unit, St. Vincent’s Institute, 9 Princes St, Fitzroy, Melbourne, 3065, Australia

    Tony Blick, Honor Hugo, Mark Waltham, Cletus Pinto & Erik W. Thompson

  2. Department of Surgery, St. Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, 3065, Australia

    Edwin Widodo, Mark Waltham, Cletus Pinto & Erik W. Thompson

  3. Faculty of Medicine, Brawijaya University, East Java, 65141, Indonesia

    Edwin Widodo

  4. Department of Molecular Pathology, Unit 951, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77054, USA

    Sendurai A. Mani

  5. Whitehead Institute for Biomedical Research, 9 Cambridge Center, and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Robert A. Weinberg

  6. Molecular Biology Department, Genentech Inc, South San Francisco, CA, 94080, USA

    Richard M. Neve

  7. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94270, USA

    Richard M. Neve & Marc E. Lenburg

  8. Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, 02118, USA

    Marc E. Lenburg

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  1. Tony Blick
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  2. Honor Hugo
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Correspondence to Erik W. Thompson.

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Supplementary Table 1

The literature pertaining to EMT in breast cancer was searched and molecules shown empirically to cause EMT or change during EMT were assembled. In some cases, additional family members were included. Gene products known to be differentially expressed across different breast cancer cell lines were not included on the basis of that alone. Although not comprehensive, EMT-SIG is an ad hoc, literature-derived gene list from the breast cancer literature. (XLS 20 kb)

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Blick, T., Hugo, H., Widodo, E. et al. Epithelial Mesenchymal Transition Traits in Human Breast Cancer Cell Lines Parallel the CD44hi/CD24lo/- Stem Cell Phenotype in Human Breast Cancer. J Mammary Gland Biol Neoplasia 15, 235–252 (2010). https://doi.org/10.1007/s10911-010-9175-z

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