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

• Published in: Oncogene Vol. 30; no. 9; pp. 1046 - 1058
• Main Authors: Henry, L A, Johnson, D A, Sarrió, D, Lee, S, Quinlan, P R, Crook, T, Thompson, A M, Reis-Filho, J S, Isacke, C M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.03.2011; Nature Publishing Group
• Subjects: 631/208/199; 631/80/86; 692/699/67/1347; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Apoptosis; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; CD105 antigen; Cell adhesion & migration; Cell Biology; Cell culture; Cell Line, Tumor; Cell migration; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Clinical outcomes; Cytoskeleton; DNA methylation; DNA Methylation - genetics; Ectopic expression; Endoglin; Endothelial cells; Epigenetics; ErbB-2 protein; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Silencing; Genetic aspects; Gynecology. Andrology. Obstetrics; Human Genetics; Humans; Internal Medicine; Invasiveness; Lung - pathology; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Membrane proteins; Metastases; Metastasis; Mice; Mice, Nude; Molecular and cellular biology; Neoplasm Invasiveness; Neoplasm Metastasis; Oncology; original-article; Patient outcomes; Physiological aspects; Polymerase Chain Reaction; Prognosis; Proteins; Receptor, ErbB-2 - metabolism; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Signal Transduction; Smad protein; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Transforming growth factors; Tumor cells; Tumors; United Kingdom; breast cancer; TGF-β; CD105; endoglin; ErbB2; MCF10A; Breast disease; Breast tumor; erbB2 Gene; Breast cancer; Malignant tumor; Metastasis; Carcinogenesis; Mammary gland diseases; C-Onc gene; TGF-P; Tumor cell; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.488

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.