Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis

Authors

  • Pasquale Pellegrini,

    1. Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain
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  • Alex Cordero,

    1. Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain
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  • Marta Ines Gallego,

    1. Laboratory of Mammary Pathology, UFIEC, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
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  • William C. Dougall,

    1. Therapeutic Innovation Unit, Amgen, Inc., Seattle, Washington, USA
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  • Muñoz Purificación,

    1. Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain
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  • Miguel Angel Pujana,

    1. Translational Research Laboratory, Breast Cancer Unit, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain
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  • Eva Gonzalez-Suarez

    Corresponding author
    1. Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain
    • Correspondence: González-Suárez Eva, Ph.D., Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Gran Via 199, L'Hospitalet de Llobregat, Barcelona 08908, Spain. Telephone: +34–932607253; Fax: +34–932607219; e-mail: egsuarez@idibell.cat

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Errata

This article is corrected by:

  1. Errata: Erratum: Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis Volume 32, Issue 2, 600, Article first published online: 13 January 2014

  • Author contributions. P.P.: collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; A.C.: collection and/or assembly of data; data analysis and interpretation; final approval of manuscript; M.I.G. and W.C.D: provision of study material, revisions of manuscript, final approval of manuscript; P.M.: revisions of manuscript, final approval of manuscript; P.A.M.: data analysis and interpretation, revisions of manuscript, final approval of manuscript; E.G.-S.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript. PP and AC contributed equally to this work.

Abstract

Receptor Activator of NF-kappa B (RANK) pathway controls mammary gland development in mice but its role in mammary stem cell fate remains undefined. We show that constitutive RANK signaling expands luminal and basal mammary compartments including mammary stem and luminal progenitor cell pools and interferes with the generation of CD61+ and Sca1+ luminal cells and Elf5 expression. Impaired mammary cell commitment upon RANK overexpression leads to the accumulation of progenitors including K14+K8+ bipotent cells and the formation of heterogeneous tumors containing hyperplastic basal, luminal, and progenitor cells. RANK expression increases in wild-type mammary epithelia with age and parity, and spontaneous preneoplastic lesions express RANK and accumulate K14+K8+ cells. In human breast tumors, high RANK expression levels are also associated with altered mammary differentiation. These results suggest that increased RANK signaling interferes with mammary cell commitment, contributing to breast carcinogenesis. Stem Cells 2013;31:1954-1965

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