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PMID: 20019840 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression.

Neoplasia (New York, N.Y.) ·Vol. 11 ·No. 12 ·2009-12-00 ·Pages 1318-28

Vesuna F, Lisok A, Kimble B, Raman V

Abstract

The cancer stem cell paradigm postulates that dysregulated tissue-specific stem cells or progenitor cells are precursors for cancer biogenesis. Consequently, identifying cancer stem cells is crucial to our understanding of cancer progression and for the development of novel therapeutic agents. In this study, we demonstrate that the overexpression of Twist in breast cells can promote the generation of a breast cancer stem cell phenotype characterized by the high expression of CD44, little or no expression of CD24, and increased aldehyde dehydrogenase 1 activity, independent of the epithelial-mesenchymal transition. In addition, Twist-overexpressing cells exhibit high efflux of Hoechst 33342 and Rhodamine 123 as a result of increased expression of ABCC1 (MRP1) transporters, a property of cancer stem cells. Moreover, we show that transient expression of Twist can induce the stem cell phenotype in multiple breast cell lines and that decreasing Twist expression by short hairpin RNA in Twist-overexpressing transgenic cell lines MCF-10A/Twist and MCF-7/Twist as well as in MDA-MB-231 partially reverses the stem cell molecular signature. Importantly, we show that inoculums of only 20 cells of the Twist-overexpressing CD44(+)/CD24(-/low) subpopulation are capable of forming tumors in the mammary fat pad of severe combined immunodeficient mice. Finally, with respect to mechanism, we provide data to indicate that Twist transcriptionally regulates CD24 expression in breast cancer cells. Taken together, our data demonstrate the direct involvement of Twist in generating a breast cancer stem cell phenotype through down-regulation of CD24 expression and independent of an epithelial-mesenchymal transition.

MeSH Terms
Aldehyde Dehydrogenase/genetics,metabolism Aldehyde Dehydrogenase 1 Family Animals Binding Sites Breast Neoplasms/genetics,metabolism,pathology CD24 Antigen/genetics,metabolism Cell Line Cell Line, Tumor Female Flow Cytometry Gene Expression Regulation, Neoplastic Humans Hyaluronan Receptors/genetics,metabolism Immunoblotting Isoenzymes/genetics,metabolism Mammary Neoplasms, Experimental/genetics,metabolism,pathology Mice Mice, SCID Neoplastic Stem Cells/metabolism,pathology Nuclear Proteins/genetics,metabolism Promoter Regions, Genetic/genetics Protein Binding RNA Interference Retinal Dehydrogenase Transcription, Genetic Transplantation, Heterologous Twist-Related Protein 1/genetics,metabolism
Chemicals
CD24 Antigen CD24 protein, human Hyaluronan Receptors Isoenzymes Nuclear Proteins TWIST1 protein, human Twist-Related Protein 1 Aldehyde Dehydrogenase 1 Family Aldehyde Dehydrogenase ALDH1A1 protein, human ALDH1A1 protein, mouse Retinal Dehydrogenase
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Vesuna Farhad
Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Traylor 338, Baltimore, MD 21205, USA.
Lisok Ala
Kimble Brian
Raman Venu
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Article Info
Journal
Neoplasia (New York, N.Y.)
Abbr.
Neoplasia
ISSN
1476-5586
DOI
10.1593/neo.91084
Published
2009-12-00
Pages
1318-28
Language
English
Region
United States
NLM ID
100886622
PMCID
PMC2794513
Subset
IM
Grants
NCI NIH HHS · P50 CA103175 · United States
NCI NIH HHS · R01 CA097226 · United States
NCI NIH HHS · R01CA097226 · United States
External Links
PubMed source DOI: 10.1593/neo.91084 PMC Full Text View journal details
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