Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome.
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.
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
L A
LA
Henry
D A
DA
Johnson
D
D
Sarrió
S
S
Lee
P R
PR
Quinlan
T
T
Crook
A M
AM
Thompson
J S
JS
Reis-Filho
C M
CM
Isacke
D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D000071063:Endoglin; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D000071063:Endoglin; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; C064206:ENG protein, human; C508053:ERBB2 protein, human