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TGFβ induces the formation of tumour-initiating cells in claudinlow breast cancer

Author

Listed:
  • Alejandra Bruna

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
    University of Cambridge, Li Ka Shing Centre)

  • Wendy Greenwood

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
    University of Cambridge, Li Ka Shing Centre)

  • John Le Quesne

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
    University of Cambridge, Li Ka Shing Centre)

  • Andrew Teschendorff

    (Medical Genomics Group, Paul O′Gorman Building, UCL Cancer Institute, University College London)

  • Diego Miranda-Saavedra

    (Bioinformatics and Genomics Laboratory, World Premier International (WPI) Immunology Frontier Research Center (IFReC), Osaka University)

  • Oscar M. Rueda

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
    University of Cambridge, Li Ka Shing Centre)

  • Jose L. Sandoval

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
    University of Cambridge, Li Ka Shing Centre)

  • Ana Tufegdzic Vidakovic

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
    University of Cambridge, Li Ka Shing Centre)

  • Amel Saadi

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
    University of Cambridge, Li Ka Shing Centre)

  • Paul Pharoah

    (Strangeways Research Laboratories, University of Cambridge, Worts Causeway
    Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University, Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research, Centre
    Cambridge Experimental Cancer Medicine Centre)

  • John Stingl

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
    University of Cambridge, Li Ka Shing Centre)

  • Carlos Caldas

    (Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
    University of Cambridge, Li Ka Shing Centre
    Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University, Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research, Centre
    Cambridge Experimental Cancer Medicine Centre)

Abstract

The role of transforming growth factor-beta (TGFβ) in the progression of different molecular subtypes of breast cancer has not been clarified. Here we show that TGFβ increases breast tumour-initiating cell (BTIC) numbers but only in claudinlow breast cancer cell lines by orchestrating a specific gene signature enriched in stem cell processes that predicts worse clinical outcome in breast cancer patients. NEDD9, a member of the Cas family of integrin scaffold proteins, is necessary to mediate these TGFβ-specific effects through a positive feedback loop that integrates TGFβ/Smad and Rho-actin-SRF-dependent signals. In normal human mammary epithelium, TGFβ induces progenitor activity only in the basal/stem cell compartment, where claudinlow cancers are presumed to arise. These data show opposing responses to TGFβ in both breast malignant cell subtypes and normal mammary epithelial cell subpopulations and suggest therapeutic strategies for a subset of human breast cancers.

Suggested Citation

  • Alejandra Bruna & Wendy Greenwood & John Le Quesne & Andrew Teschendorff & Diego Miranda-Saavedra & Oscar M. Rueda & Jose L. Sandoval & Ana Tufegdzic Vidakovic & Amel Saadi & Paul Pharoah & John Sting, 2012. "TGFβ induces the formation of tumour-initiating cells in claudinlow breast cancer," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2039
    DOI: 10.1038/ncomms2039
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    Cited by:

    1. Christopher R S Banerji & Simone Severini & Carlos Caldas & Andrew E Teschendorff, 2015. "Intra-Tumour Signalling Entropy Determines Clinical Outcome in Breast and Lung Cancer," PLOS Computational Biology, Public Library of Science, vol. 11(3), pages 1-23, March.

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