The TGF-β/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system

Wiercinska, Eliza; Naber, Hildegonda P. H.; Pardali, Evangelia; Pluijm, Gabri van der; Dam, Hans van; Dijke, Peter ten

doi:10.1007/s10549-010-1147-x

Cited by 185 publications

(158 citation statements)

References 54 publications

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“…EMT recently has been implicated in the acquisition of cancer stem cell properties (12) and resistance to conventional therapies (13). TGF-β inhibits the expression of epithelial genes, such as E-cadherin, and induces the expression of mesenchymal genes such as vimentin and extracellular matrix-degrading proteases (14), including the urokinase-type plasminogen activator (uPA) (15) and various matrix metallopeptidases (MMPs) (16).…”

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confidence: 99%

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

Risolino

Mandia

Iavarone

et al. 2014

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

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Pre-B-cell leukemia homeobox (Pbx)-regulating protein-1 (Prep1) is a ubiquitous homeoprotein involved in early development, genomic stability, insulin sensitivity, and hematopoiesis. Previously we have shown that Prep1 is a haploinsufficient tumor suppressor that inhibits neoplastic transformation by competing with myeloid ecotropic integration site 1 for binding to the common heterodimeric partner Pbx1. Epithelial-mesenchymal transition (EMT) is controlled by complex networks of proinvasive transcription factors responsive to paracrine factors such as TGF-β. Here we show that, in addition to inhibiting primary tumor growth, PREP1 is a novel EMT inducer and prometastatic transcription factor. In human non-small cell lung cancer (NSCLC) cells, PREP1 overexpression is sufficient to trigger EMT, whereas PREP1 down-regulation inhibits the induction of EMT in response to TGF-β. PREP1 modulates the cellular sensitivity to TGF-β by inducing the small mothers against decapentaplegic homolog 3 (SMAD3) nuclear translocation through mechanisms dependent, at least in part, on PREP1-mediated transactivation of a regulatory element in the SMAD3 first intron. Along with the stabilization and accumulation of PBX1, PREP1 induces the expression of multiple activator protein 1 components including the proinvasive Fos-related antigen 1 (FRA-1) oncoprotein. Both FRA-1 and PBX1 are required for the mesenchymal changes triggered by PREP1 in lung tumor cells. Finally, we show that the PREP1-induced mesenchymal transformation correlates with significantly increased lung colonization by cells overexpressing PREP1. Accordingly, we have detected PREP1 accumulation in a large number of human brain metastases of various solid tumors, including NSCLC. These findings point to a novel role of the PREP1 homeoprotein in the control of the TGF-β pathway, EMT, and metastasis in NSCLC.TALE proteins | PTGFβ P REP1 [pre-B-cell leukemia homeobox (Pbx)-regulating protein-1], also known as "PKNOX1" (PBX/knotted homeobox 1), belongs to the TALE (three-amino acid-loop-extension) family of homeodomain transcription factors, along with myeloid ecotropic integration site (MEIS) and PBX proteins. As indicated by its name, PREP1 retains PBX1 in the nucleus and induces its binding to DNA (1).PREP1 is essential in embryonic development. Although Prep1-null embryos die before gastrulation from apoptosis of the epiblast (2), hypomorphic Prep1-mutant mice (Prep i/i ), expressing severely decreased Prep1 levels (3-10% of wild-type) exhibit incompletely penetrant embryonic phenotypes, mainly characterized by alterations in hematopoiesis and angiogenesis (3).Prep1 deficiency affects cell proliferation and survival in various biological contexts. Decreased Prep1 expression results in increased apoptosis in Prep1 i/i embryos and mouse embryonic fibroblasts (MEFs) (4). In Prep1 −/− embryos, early preimplantation lethality is consequent to increased apoptosis in mouse pluripotent epiblast cells. Genetic analysis suggests that the lack of Prep1 confers increased sensitivity...

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confidence: 99%

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

Risolino

Mandia

Iavarone

et al. 2014

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

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“…In addition, SMAD4 inactivation within an evolving neoplasm may indirectly influence the extracellular matrix to promote tumor growth. This was confirmed by a study, which found that TGF-β/SMAD induced breast cancer cell invasion via upregulation of MMP2 and 9 by TGF-β in a SMAD4-dependent manner (27).…”

Section: Discussionmentioning

confidence: 60%

“…The dichotomous function of TGF-β in breast cancer progression has been attributed to aberrant expression of SMAD4 or disruption of SMAD4 activity, which has been demonstrated to switch TGF-β from a repressor to an activator of ERα trans-activation (25). Furthermore, it has been reported that SMAD4/TGF-β-induced breast cancer cell invasion occurred via the upregulation of matrix metalloproteinase (MMP)-2 and -9 (27). Although there have been numerous studies investigating the role of SMAD4 in the tumorigenesis and progression of breast cancer (28)(29)(30)(31), there is currently very limited information regarding the expression of SMAD4 in human breast cancer tissues and its potential prognostic significance.…”

Section: Introductionmentioning

confidence: 99%

SMAD4 expression in breast ductal carcinoma correlates with prognosis

Liu

Shi

et al. 2015

Oncology Letters

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Abstract. The present study examined SMAD4 expression in fine-needle aspiration cell blocks from patients with breast ductal carcinoma, in order to assess its viability as a prognostic marker. Using immunohistochemistry, the SMAD4 protein status of 86 breast ductal carcinoma fine-needle biopsies, from patients who underwent tumor resection at Beihua University Affiliated Hospital (Jilin, China) between 2002 and 2008, was characterized. The association between SMAD4 expression and clinicopathological parameters, as well as prognosis was assessed using the Mantel-Haenszel method and Cox proportional hazards regression. SMAD4 staining was observed in the cytoplasm and nucleus, and its expression was found to be decreased in ductal breast carcinoma as compared with adjacent normal breast epithelia. Patients with reduced SMAD4 expression levels tended to exhibit more poorly differentiated tumors, a higher risk of recurrence and shorter overall survival. These results demonstrated that the evaluation of SMAD4 protein status in fine-needle biopsy specimens of breast ductal carcinoma may provide additional prognostic information.

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“…mmPs play a crucial role in cancer cell invasion and metastasis. mmP-9, which degrades basement membrane collagen, has been shown to promote tumor cell invasion and metastasis and decrease survival in many types of cancer (29,39). It has been generally accepted that tumor angiogenesis plays a critical role in tumor growth, invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%