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Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome

Oncogene volume 30, pages 1046–1058 (2011)Cite this article

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Abstract

Tumor growth factor-β (TGF-β) signaling in cancer has been implicated in growth suppression of early lesions and enhancing tumor cell invasion and metastasis. However, the cellular mechanisms that determine this signaling output in individual tumors are still largely unknown. In endothelial cells, TGF-β signaling is modulated by the TGF-β co-receptor endoglin (CD105). Here we demonstrate that endoglin is expressed in a subset of invasive breast cancers and cell lines and is subject to epigenetic silencing by gene methylation. Endoglin downregulation in non-tumorigenic MCF10A breast cells leads to the formation of abnormal acini in 3D culture, but does not promote cell migration or transformation. In contrast, in the presence of activated ErbB2, endoglin downregulation in MCF10A cells leads to enhanced invasion into a 3D matrix. Consistent with these data, ectopic expression of endoglin in MDA-MB-231 cells blocks TGF-β-enhanced cell motility and invasion and reduces lung colonization in an in vivo metastasis model. Unlike endothelial cells, endoglin does not modulate Smad-mediated TGF-β signaling in breast cells but attenuates the cytoskeletal remodeling to impair cell migration and invasion. Importantly, in a large cohort of invasive breast cancers, lack of endoglin expression in the tumor cell compartment correlates with ENG gene methylation and poor clinical outcome.

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Acknowledgements

We thank Kay Savage and Suzanne Parry for immunohistochemical staining, Reshma Shah for help with the methylation analysis, Caterina Marchio for microdissection, Senthil Muthuswamy for the MCF10A.ErbB2 cells and Ariad Pharmaceuticals (www.ariad.com/regulationkits) for the AP1510 reagent. This project was funded by Breakthrough Breast Cancer and from NHS funding to the NIHR Biomedical Research Centre, a Marie Curie Intra-European Fellowship (PIEF-GA-2008-221083) and Breast Cancer Research Scotland with support from the Tayside Tissue Bank.

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Authors and Affiliations

  1. Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK

    L A Henry, D A Johnson, D Sarrió, S Lee, T Crook, J S Reis-Filho & C M Isacke

  2. Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee, UK

    P R Quinlan & A M Thompson

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  1. L A Henry
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  2. D A Johnson
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Correspondence to C M Isacke.

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Henry, L., Johnson, D., Sarrió, D. et al. Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome. Oncogene 30, 1046–1058 (2011). https://doi.org/10.1038/onc.2010.488

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  • DOI: https://doi.org/10.1038/onc.2010.488

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