Aldehyde Dehydrogenase Activity of Breast Cancer Stem Cells Is Primarily Due To Isoform ALDH1A3 and Its Expression Is Predictive of Metastasis§

Authors

  • Paola Marcato,

    1. Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    Search for more papers by this author
  • Cheryl A. Dean,

    1. Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    Search for more papers by this author
  • Da Pan,

    1. Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    Search for more papers by this author
  • Rakhna Araslanova,

    1. Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    Search for more papers by this author
  • Megan Gillis,

    1. Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    Search for more papers by this author
  • Madalsa Joshi,

    1. Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    Search for more papers by this author
  • Lucy Helyer,

    1. Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    Search for more papers by this author
  • Luzhe Pan,

    1. Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    Search for more papers by this author
  • Andrew Leidal,

    1. Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    Search for more papers by this author
  • Shashi Gujar,

    1. Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    Search for more papers by this author
  • Carman A. Giacomantonio,

    Corresponding author
    1. Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    • Department of Surgery, Dalhousie University, Rm 828 Victoria Building, QEII HSC, 1278 Tower Road, Halifax, Nova Scotia, Canada B3H 2Y9
    Search for more papers by this author
    • Telephone: 1-902-473-6177; Fax: 1-902-473-6178

  • Patrick W. K. Lee

    Corresponding author
    1. Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    2. Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    • Department of Microbiology and Immunology, Dalhousie University, Rm 7P, Sir Charles Tupper Medical Bldg., 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5
    Search for more papers by this author
    • Telephone: 1-902-494-8048; Fax: 1-902-494-5125


  • Author contributions: P. M.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; C.A.D.: collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; D.P.: collection and/or assembly of data, final approval of manuscript; R.A.: collection and/or assembly of data, collection and/or assembly of data, final approval of manuscript; M.G.: collection and/or assembly of data, final approval of manuscript; M.J.: collection and/or assembly of data, final approval of manuscript; L.H.: provision of study material or patients, final approval of manuscript; L.P.: collection and/or assembly of data, final approval of manuscript; A.L.: collection and/or assembly of data, final approval of manuscript; S.G.: collection and/or assembly of data, final approval of manuscript; C.A.G.: conception and design, financial support, provision of study material or patients, final approval of manuscript; P.W.K.L.: conception and design, financial support, data analysis and interpretation, manuscript writing.

  • First published online in STEM CELLS EXPRESS November 23, 2010.

  • §

    Disclosure of potential conflicts of interest is found at the end of this article.

Abstract

Cancer stem cells (CSCs) are proposed to initiate cancer and propagate metastasis. Breast CSCs identified by aldehyde dehydrogenase (ALDH) activity are highly tumorigenic in xenograft models. However, in patient breast tumor immunohistological studies, where CSCs are identified by expression of ALDH isoform ALDH1A1, CSC prevalence is not correlative with metastasis, raising some doubt as to the role of CSCs in cancer. We characterized the expression of all 19 ALDH isoforms in patient breast tumor CSCs and breast cancer cell lines by total genome microarray expression analysis, immunofluorescence protein expression studies, and quantitative polymerase chain reaction. These studies revealed that ALDH activity of patient breast tumor CSCs and cell lines correlates best with expression of another isoform, ALDH1A3, not ALDH1A1. We performed shRNA knockdown experiments of the various ALDH isoforms and found that only ALDH1A3 knockdown uniformly reduced ALDH activity of breast cancer cells. Immunohistological studies with fixed patient breast tumor samples revealed that ALDH1A3 expression in patient breast tumors correlates significantly with tumor grade, metastasis, and cancer stage. Our results, therefore, identify ALDH1A3 as a novel CSC marker with potential clinical prognostic applicability, and demonstrate a clear correlation between CSC prevalence and the development of metastatic breast cancer. STEM CELLS 2011;29:32–45

Ancillary