Endoglin expression in metastatic breast cancer cells enhances their invasive phenotype

Oxmann, Daniel; Held‐Feindt, Janka; Stark, Andreas M.; Hattermann, Kirsten; Yoneda, Toshiyuki; Mentlein, Rolf

doi:10.1038/sj.onc.1211025

Cited by 71 publications

(48 citation statements)

References 25 publications

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“…The reasons for these differing effects on TGF-b signaling are not known but may reflect differing mechanisms regulating the interplay between endoglin and TGF-b in squamous carcinomas versus prostate/breast carcinomas. Surprisingly, a pro-invasive role for endoglin has been reported recently in MDA-MB-231 cells in vitro (Oxmann et al, 2008), which is in direct contrast to the in vitro and in vivo findings reported here. However, it should be noted that these authors performed their scratch-wound migration and Boyden-chamber invasion assays over a 3-h period and therefore may be monitoring a short-term cellular phenotype rather than cell migration/invasion.…”

Section: Discussioncontrasting

confidence: 99%

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

et al. 2010

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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.

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Section: Discussioncontrasting

confidence: 99%

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

et al. 2010

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“…Another protein, able to induce invadopodia and also involved in EMT, is endoglin, a cell surface adhesion molecule and coreceptor for TGFβ signaling [224]. Endoglin is needed for EMT during heart development, and its expression correlates with increased invasiveness of breast cancer cells via the increased formation of invadopodia [198,225].…”

Section: Invadopodia and Their Role In Emtmentioning

confidence: 99%

“…Invadopodia have been identified in numerous cancer cell lines, including malignant melanoma, breast cancer, glioma, and head and neck cancer [193][194][195][196]. The formation of invadopodia can be initiated by various signals, for example by EGF, HGF or TGFβ-induced signal transduction [193,197,198] or by α 6 β 1 -integrin engagement [199]. Invadopodia-inducing Integrins (like α v β 3 -integrin), along with their cytoplasmic interaction partners, are positioned in the adhesive ring where they mediate adhesion.…”

Section: Podosomes and Invadopodiamentioning

confidence: 99%

EMT, the cytoskeleton, and cancer cell invasion

Yilmaz

Christofori

2009

Cancer Metastasis Rev

1,533

1,314

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The metastatic process, i.e. the dissemination of cancer cells throughout the body to seed secondary tumors at distant sites, requires cancer cells to leave the primary tumor and to acquire migratory and invasive capabilities. In a process of epithelial-mesenchymal transition (EMT), besides changing their adhesive repertoire, cancer cells employ developmental processes to gain migratory and invasive properties that involve a dramatic reorganization of the actin cytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. The molecular processes underlying such cellular changes are still only poorly understood, and the various migratory organelles, including lamellipodia, filopodia, invadopodia and podosomes, still require a better functional and molecular characterization. Notably, direct experimental evidence linking the formation of migratory membrane protrusions and the process of EMT and tumor metastasis is still lacking. In this review, we have summarized recent novel insights into the molecular processes and players underlying EMT on one side and the formation of invasive membrane protrusions on the other side.

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“…Together, these data indicate that mutp53 docks onto Sp1 to increase ENTPD5 promoter activity. To explore whether mutp53 and ENTPD5 enhance folding and maturation of N-glycoproteins, we investigated endoglin/CD105, a coreceptor for TGFβ that is implicated in migration, invasion, and metastasis of breast and pancreatic cancer cells (19,31,32). Endoglin function relies exquisitely on protein folding in the calnexin/calreticulin cycle because endoglin mutants that colocalize with calnexin in the ER cause hereditary hemorrhagic telangiectasia (33,34).…”

Section: Entpd5 Expression Levels Correlate With Gof P53 In Human Tumormentioning

confidence: 99%

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

Vogiatzi

Brandt

Schneikert

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5′-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.M utations in the TP53 tumor suppressor gene are the most frequent genetic alterations in human cancer and commonly compromise the gene's tumor suppressor activity. p53-knockout mice succumb to tumors very early in life, arguing that the loss of function associated with p53 mutations is sufficient on its own to explain the high mutation frequency observed in patients with cancer (1). However, in striking contrast to mutations in other tumor suppressor genes, the vast majority of TP53 gene alterations in patients with cancer neither ablate p53 expression nor produce unstable or truncated proteins. Instead, p53 mutations are mostly missense mutations resulting in expression of mutant p53 (mutp53) proteins with only single-amino acid substitutions that accumulate to steady-state levels greatly exceeding those of wild-type p53 (wtp53) in normal tissues. Immunohistochemical positivity for p53 is therefore considered a diagnostic marker for the presence of a TP53 mutation (2). The high prevalence of missense mutations suggests a selective advantage during cancer progression, so it was hypothesized early on in p53 research that p53 mutations are neomorphic and endow the mutp53 protein with novel oncogenic functions that actively promote cancer progression and therapy resistance (2). These oncogenic properties are generally referred to as the mutp53 gain of function (GOF).Over the years, substantial experimental evidence for mutp53 GOF has accumulated (3-5). For example, mice expressing cancer-associated p53 hot spot mutations from the endogenous Trp53 gene locus are remarkably different from p53-deficient mice: tumorigenesis is accelerated, and the spectrum of tumors is shifted toward carcinomas and more meta...

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Endoglin expression in metastatic breast cancer cells enhances their invasive phenotype

Cited by 71 publications

References 25 publications

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

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

EMT, the cytoskeleton, and cancer cell invasion

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

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