Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome. / Henry, L. A.; Johnson, D. A.; Sarrio, D.; Lee, S.; Quinlan, P.R.; Crook, T.; Thompson, A.M.; Reis-Filho, J. S.; Isacke, C. M.
In: Oncogene, Vol. 30, No. 9, 03.2011, p. 1046-1058.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome
A1 - Henry,L. A.
A1 - Johnson,D. A.
A1 - Sarrio,D.
A1 - Lee,S.
A1 - Quinlan,P.R.
A1 - Crook,T.
A1 - Thompson,A.M.
A1 - Reis-Filho,J. S.
A1 - Isacke,C. M.
AU - Henry,L. A.
AU - Johnson,D. A.
AU - Sarrio,D.
AU - Lee,S.
AU - Quinlan,P.R.
AU - Crook,T.
AU - Thompson,A.M.
AU - Reis-Filho,J. S.
AU - Isacke,C. M.
PY - 2011/3
Y1 - 2011/3
N2 - <p>Tumor growth factor-beta (TGF-beta) 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-beta signaling is modulated by the TGF-beta 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-beta-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-beta 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. Oncogene (2011) 30, 1046-1058; doi:10.1038/onc.2010.488; published online 1 November 2010</p>
AB - <p>Tumor growth factor-beta (TGF-beta) 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-beta signaling is modulated by the TGF-beta 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-beta-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-beta 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. Oncogene (2011) 30, 1046-1058; doi:10.1038/onc.2010.488; published online 1 November 2010</p>
KW - endoglin
KW - CD105
KW - breast cancer
KW - TGF-beta
KW - MCF10A
KW - ErbB2
KW - GROWTH-FACTOR-BETA
KW - MOUSE SKIN CARCINOGENESIS
KW - TGF-BETA
KW - ENDOTHELIAL-CELLS
KW - TRANSFORMING GROWTH-FACTOR-BETA-1
KW - RECEPTOR
KW - CANCER
KW - MIGRATION
KW - PROLIFERATION
KW - ACTIVATION
U2 - 10.1038/onc.2010.488
DO - 10.1038/onc.2010.488
M1 - Article
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 9
VL - 30
SP - 1046
EP - 1058
ER -