P-Cadherin Is Coexpressed with CD44 and CD49f and Mediates Stem Cell Properties in Basal-like Breast Cancer§

Authors

  • André Filipe Vieira,

    1. IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
    2. ICBAS—Abel Salazar Biomedical Sciences Institute, Porto, Portugal
    3. Breast Biology Group, School of Cancer and Enabling Sciences, University of Manchester, Manchester, United Kingdom
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  • Sara Ricardo,

    1. IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
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  • Matthew Paul Ablett,

    1. Breast Biology Group, School of Cancer and Enabling Sciences, University of Manchester, Manchester, United Kingdom
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  • Maria Rita Dionísio,

    1. IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
    2. Gulbenkian Programme for Advanced Medical Education, Vigo, Spain
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  • Nuno Mendes,

    1. IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
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  • André Albergaria,

    1. IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
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  • Gillian Farnie,

    1. Breast Biology Group, School of Cancer and Enabling Sciences, University of Manchester, Manchester, United Kingdom
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  • Renê Gerhard,

    1. IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
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  • Jorge F. Cameselle-Teijeiro,

    1. Complexo Hospitalar Universitario de Vigo (CHUVI), Vigo, Spain
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  • Raquel Seruca,

    1. IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
    2. Faculty of Medicine of the University of Porto, Porto, Portugal
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  • Fernando Schmitt,

    1. IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
    2. Faculty of Medicine of the University of Porto, Porto, Portugal
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  • Robert B. Clarke,

    1. Breast Biology Group, School of Cancer and Enabling Sciences, University of Manchester, Manchester, United Kingdom
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  • Joana Paredes

    Corresponding author
    1. IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
    2. Faculty of Medicine of the University of Porto, Porto, Portugal
    • IPATIMUP—Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal
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    • Telephone: +351-22-5570700; Fax: +351-22-5570799


  • Author contributions: A.F.V.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; S.R.: collection and/or assembly of data and data analysis and interpretation; M.P.A., M.R.D., and N.M.: collection and/or assembly of data; A.A., G.F., R.G., R.S., and F.S.: data analysis and interpretation; J.F.C.-T.: provision of study material or patients; R.B.C.: conception and design, provision of study material or patients, and data analysis and interpretation; J.P.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript.

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

  • §

    First published online in STEM CELLSEXPRESS March 2, 2012.

Abstract

Although the luminal progenitor cell of the normal mammary gland hierarchy has been proposed as the cell-of-origin for basal-like breast cancers, finding the cancer stem cell (CSC) phenotype for this malignancy has proven a difficult task, mostly due to the lack of specific markers. Recently, basal-like sporadic and familial cases of breast cancer have been linked to BRCA1 gene inactivation, which enables the upregulation of the target-repressed CDH3/P-cadherin gene, an important biomarker of basal-like breast carcinomas. Previously, we demonstrated that P-cadherin overexpression can mediate aggressive behavior in these tumors. Thus, our aim was to test whether P-cadherin mediates stem cell properties in basal-like breast carcinomas. Using a series of breast cancer cell lines and primary tumors, we showed that P-cadherin was directly associated with the expression of the breast stem markers CD44, CD49f, and aldehyde dehydrogenase 1 in the basal subtype. Moreover, cell population enriched for P-cadherin expression comprised increased in vitro mammosphere-forming efficiency and capacity to grow colonies in three-dimensional cultures as well as greater tumorigenicity. Importantly, an association was found with stem-/progenitor-like phenotypes of the breast, including the luminal progenitor population, CD49f+CD24+. Additionally, P-cadherin expression conferred resistance to x-ray-induced cell death, sustaining a role for this molecule in another stem cell property. In summary, we demonstrated, for the first time, that P-cadherin mediates stem cell properties, which could be explored in order to better define the CSC phenotype of basal-like breast tumors and the cell-of-origin of this malignancy. STEM CELLS 2012;30:854–864

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