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

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 Stingl and Carlos Caldas ()
Additional contact information
Alejandra Bruna: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
Wendy Greenwood: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
John Le Quesne: Cancer Research UK, Cambridge Research Institute, 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
Jose L. Sandoval: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
Ana Tufegdzic Vidakovic: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
Amel Saadi: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
Paul Pharoah: Strangeways Research Laboratories, University of Cambridge, Worts Causeway
John Stingl: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre
Carlos Caldas: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms2039

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