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

Abstract

Tumor growth factor-b (TGF-b) 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-b signaling is modulated by the TGF-b coreceptor 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-b-enhanced cell motility and invasion and reduces lung colonization in an in vivo metastasis model. Unlike endothelial cells, endoglin does not modulate Smadmediated TGF-b 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.

PRH/HHex inhibits the migration of breast and prostate epithelial cells through direct transcriptional regulation of Endoglin

“…However, it has been reported that Endoglin expression is higher in metastatic cancer epithelial cells and prostatic intraepithelial neoplasia compared to benign or normal prostate cells (38). Moreover, in highly metastatic breast cancer cells increased Endoglin expression is associated with invasion and metastasis (23). We expect that the regulation of Endoglin by PRH is disrupted in breast cancer cells.…”

“…We conclude that in both breast and prostate cells PRH regulates Endoglin expression and that the effects of PRH on cell migration are in part at least through the control of this target gene. Endoglin has been shown to inhibit cell migration, cell invasion and tumour growth by prostate cancer cells and cell migration and invasion of breast cancer cells (18,23). However, it has been reported that Endoglin expression is higher in metastatic cancer epithelial cells and prostatic intraepithelial neoplasia compared to benign or normal prostate cells (38).…”

“…Moreover, Endoglin inhibits the migration and invasion of breast tumour cells in vivo by modulating cytoskeletal remodeling rather than through TGF co-receptor modulation and low Endoglin expression correlates with poor prognosis in a panel of invasive breast tumours (23).…”

Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial

“…The exploratory analyses suggesting effects of metformin on key cellular pathways is in keeping with the prominence of transforming growth factor beta (TGFB) up-regulation (identified in the Tumour Necrosis Factor Receptor 1 (TNFR1) signaling pathway) for the inhibition of breast cancer [29] and conversely the failure of the TGFB pathways in the resistance of breast cancer to tamoxifen [30] . This suggests potential synergism between metformin and established breast cancer therapies.…”

PAK1 Tyrosine Phosphorylation Is Required to Induce Epithelial–Mesenchymal Transition and Radioresistance in Lung Cancer Cells

“…A549 and NCI-H460 cells were grown on a thick layer of Matrigel to form epithelial acini (3D culture model). This system has been used extensively to identify morphologic changes that can perturb the normal cancer growth architecture (33,34). In this 3D culture model, irradiated NSCLC cells were distinguishable from the control cells and formed an increased number of acini that invaded the Matrigel-containing 3D matrix.…”