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Transforming growth factor-beta (TGFβ) signaling in cancer has been implicated in both growth suppression in early lesions as well as enhancing tumor cell invasion and metastasis. However, the cellular mechanisms that determine the signaling output in individual tumors are still largely unknown. In endothelial cells, TGFβ signaling is modulated by the TGFβ co-receptor endoglin (CD105). Here we demonstrate that endoglin is differentially expressed in invasive breast cancers and breast cancer cell lines, and is subject to epigenetic silencing by gene methylation. Downregulation of endoglin expression in nontumorigenic MCF10A cells leads to the formation of abnormal acini in 3D culture but does not promote cell migration or result in cell transformation. In contrast, in the presence of an activated oncogene, loss of endoglin in MCF10A cells leads to enhanced migration and invasion into a 3D matrix. Consistent with these data, ectopic expression of endoglin in the endoglin-negative MDA-MB-231 cell line blocks TGFβ-enhanced cell motility and invasion and reduces the ability of cells to successfully colonize the lung parenchyma in an in vivo metastasis model. Unlike endothelial cells, endoglin does not does not modulate canonical TGFβ signaling in breast cells but attenuates the cytoskeletal remodeling to impair cell migration and invasion. Importantly, lack of endoglin expression in clinical samples significantly correlates with ENG gene methylation and poor clinical outcome. Together these data identify endoglin as a key component suppressing the invasive activities of breast cancer cells.