The EMT-activator ZEB1 induces bone metastasis associated genes including BMP-inhibitors

Mock, Kerstin; Preca, Bogdan‐Tiberius; Brummer, Tilman; Brabletz, Simone; Stemmler, Marc P.; Brabletz, Thomas

doi:10.18632/oncotarget.3882

Cited by 50 publications

(56 citation statements)

References 53 publications

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“…Recent findings support the notion that ZEB1 not only acts as a transcriptional repressor to suppress epithelial-specific genes like E-cad and members of the miR-200 family, but can also activate transcription in specific contexts by interacting with different co-factors [9, 11]. Interestingly, this function of ZEB1 does not necessarily require direct binding of ZEB1 to the DNA.…”

Section: Discussionsupporting

confidence: 60%

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A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer

et al. 2017

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Cancer metastasis is the main reason for poor patient survival. Tumor cells delaminate from the primary tumor by induction of epithelial-mesenchymal transition (EMT). EMT is mediated by key transcription factors, including ZEB1, activated by tumor cell interactions with stromal cells and the extracellular matrix (ECM). ZEB1-mediated EMT and motility is accompanied by substantial cell reprogramming and the acquisition of a stemness phenotype. However, understanding of the underlying mechanism is still incomplete. We identified hyaluronic acid (HA), one major ECM proteoglycan and enriched in mammary tumors, to support EMT and enhance ZEB1 expression in cooperation with CD44s. In breast cancer cell lines HA is synthesized mainly by HAS2, which was already shown to be implicated in cancer progression. ZEB1 and HAS2 expression strongly correlates in various cancer entities and high HAS2 levels associate with an early relapse. We identified HAS2, tumor cell-derived HA and ZEB1 to form a positive feedback loop as ZEB1, elevated by HA, directly activates HAS2 expression. In an in vitro differentiation model HA-conditioned medium of breast cancer cells is enhancing osteoclast formation, an indicator of tumor cell-induced osteolysis that facilitates formation of bone metastasis. In combination with the previously identified ZEB1/ESRP1/CD44s feedback loop, we found a novel autocrine mechanism how ZEB1 is accelerating EMT.

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Section: Discussionsupporting

confidence: 60%

“…ZEB1 was shown to induce the expression of the BMP inhibitors NOG, FOL and CHRDL1, which are secreted and known to promote osteolysis [11, 47]. Hence, HA and BMP inhibitors cooperate in bone remodeling.…”

Section: Discussionmentioning

confidence: 99%

A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer

et al. 2017

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“…ZEB1 expression directly promotes BMP-inhibitor gene transcription and indirectly suppresses BMP-inhibitor reduction via miR-200 family members. As a result, ZEB1 expression leads to BMP-inhibitor mediated osteoclast differentiation [63]. In colon cancer cells, HIF-1α directly binds to a hypoxia response element (HRE) in the proximal promoter of ZEB1 causing an increase in the transactivation and expression of ZEB1.…”

Section: Hypoxia Epithelial-to-mesenchymal Transition (Emt) and mentioning

confidence: 99%

“…Hypoxia induces increased expression and activity of MMP-2 and MMP-9 through a HIF-1-dependent process (Figure 1) [60,61], and increased levels of MMP-2 in breast cancer biopsies were associated with poor prognosis [62]. In addition to secreted MMPs, which are activated by extracellular proteolytic cleavage, hypoxia also induces the membrane bound MT1-MMP in cancer cells by direct binding of HIF-2 to an HRE in the MMP14 gene locus [63]. …”

Section: Hif Regulation Of Invasion and Intravasationmentioning

confidence: 99%

Implications of Hypoxia in Breast Cancer Metastasis to Bone

Gilkes

2016

IJMS

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Most solid tumors contain regions of hypoxia in which increased cell proliferation promotes increased oxygen consumption and the condition is further exacerbated as cancer cells become localized far from a functional blood vessel, further decreasing the oxygen supply. An important mechanism that promotes cell adaptation to hypoxic conditions is the expression of hypoxia-inducible factors (HIFs). Hypoxia-inducible factors transcriptionally regulate many genes involved in the invasion and metastasis of breast cancer cells. Patients, whose primary tumor biopsies show high HIF expression levels, have a greater risk of metastasis. The current review will highlight the potential role of hypoxia in breast cancer metastasis to the bone by considering the regulation of many steps in the metastatic process that include invasion, migration, margination and extravasation, as well as homing signals and regulation of the bone microenvironment.

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“…BMP-7 also inhibited cholangiocarcinoma cell migration by suppressing TGF-β-mediated Twist expression, which is an important EMT transcription factor [69]. Accordingly, the effects of BMPs reversing EMT have been determined in breast cancer cells where BMP signaling induced E-cadherin expression and limited cancer cell metastatic potential by repressing EMT-activator Zeb1genes [70]. …”

Section: Bilateral Roles Of Bmp Signaling In Cellular Events Of Carcimentioning

confidence: 99%

BMP signaling and its paradoxical effects in tumorigenesis and dissemination

Zhang

Long

et al. 2016

Oncotarget

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Bone morphogenetic proteins (BMPs) play important roles in embryonic and postnatal development by regulating cell differentiation, proliferation, motility, and survival, thus maintaining homeostasis during organ and tissue development. BMPs can lead to tumorigenesis and regulate cancer progression in different stages. Therefore, we summarized studies on BMP expression, the clinical significance of BMP dysfunction in various cancer types, and the molecular regulation of various BMP-related signaling pathways. We emphasized on the paradoxical effects of BMPs on various aspects of carcinogenesis, including epithelial–mesenchymal transition (EMT), cancer stem cells (CSCs), and angiogenesis. We also reviewed the molecular mechanisms by which BMPs regulate tumor generation and progression as well as potential therapeutic targets against BMPs that might be valuable in preventing tumor growth and invasion.

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The EMT-activator ZEB1 induces bone metastasis associated genes including BMP-inhibitors

Cited by 50 publications

References 53 publications

A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer

A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer

Implications of Hypoxia in Breast Cancer Metastasis to Bone

BMP signaling and its paradoxical effects in tumorigenesis and dissemination

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