ERM/ETV5 Up-regulation Plays a Role during Myometrial Infiltration through Matrix Metalloproteinase-2 Activation in Endometrial Cancer

Monge, Marta; Colás, Eva; Doll, Andreas; González, Marta; Gil‐Moreno, Antonio; Planagumà, Jesús; Quiles, Maite; Arbós, M.A.; García, Ángel; Castellví, Josep; Llauradó, Marta; Rigau, Marina; Alazzouzi, Hafid; Xercavins, Jordi; Alameda, Francesc; Reventós, Jaume; Abal, Miguel

doi:10.1158/0008-5472.can-06-4487

Cited by 55 publications

(79 citation statements)

References 28 publications

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“…35 Interestingly, we have previously described the Ets family member ERM/ETV5, specifically upregulated in endometrial cancer associated with an initial switch to myometrial infiltration, acting through MMP-2 gelatinolytic activity to confer invasive capabilities. 6,7,36 Further work must be performed to fully characterize the mechanisms underlying the promotion of distant metastasis by RUNX1 modulation.…”

Section: Discussionmentioning

confidence: 99%

“…7 pEGFP-C2 vector was purchased from BD Biosciences (Franklin Lakes, NJ). Plasmid construction consisted of the full-length human RUNX1 being removed with EcoRI from a pSV-hRUNX1 construct; it was then inserted at the EcoRI position at the multiple cloning site of the pEGFP-C2 vector.…”

Section: Cell Lines Constructs and Stable Transfectionmentioning

confidence: 99%

“…3,4 The precise molecular events that occur during the development, progression/invasion and formation of metastasis in endometrial carcinoma are largely uncharacterized and are still relatively poorly understood. [5][6][7][8] Experimental models based on human endometrial adenocarcinoma cells are widely used; the existing animal-derived models mainly use subcutaneous xenografts, injecting tumor cells into the subcutis of nude rodents. 9 Although there is evidence that these models can predict clinical efficacy, they still have significant limitations, which make the development of more complex models desirable.…”

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confidence: 99%

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An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis

Doll

González

Abal

et al. 2009

Intl Journal of Cancer

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Endometrial carcinoma is the most common malignancy of the female genital tract in industrialized countries. Metastasis is the major cause of endometrial cancer deaths. Therefore, there is a vital need for clinically relevant in vivo models allowing the elucidation of the molecular and cellular mechanisms underlying metastatic behavior. In this study, we describe an innovative experimental orthotopic model of human endometrial carcinoma. Implantation in the bifurcation of the uterine horns resulted in tumors integrated into the myometrial compartment, which can be used and further exploited for the study of in vivo angiogenesis, myometrial invasion, and the metastatic capacity of endometrial cancer cells. This orthotopic model also represents a suitable tool to analyze how tumorigenesis and distant metastasis of endometrial cancer might be influenced by gene alteration, by modulating its expression in the original cancer cell line. One of the candidate genes implicated in endometrial cancer is the transcription factor RUNX1. The over-expression of RUNX1 in the endometrial cancer cell line HEC1A and the transplantation of these cells to the uterus of nude mice were associated specifically with distant metastasis in the lung. RUNX1 plays a role in the establishment of metastases in endometrial cancer. Translated to the clinics, these models would be equivalent to an advanced undifferentiated carcinoma with node affectation (stage IIIC) and distant metastasis (stage IVB). These patients would be candidates for adjuvant therapy, not efficient until today, and therefore, our models are actually suitable for the design and evaluation of experimental therapies. ' 2009 UICC

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Section: Discussionmentioning

confidence: 99%

Section: Cell Lines Constructs and Stable Transfectionmentioning

confidence: 99%

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confidence: 99%

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An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis

Doll

González

Abal

et al. 2009

Intl Journal of Cancer

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“…HEC-1A endometrial carcinoma cells were cultured as described (14), and RL95-2 endometrial adenosquamous carcinoma cells were grown in DMEM/F12 medium containing 10% FBS and 1% penicillin/streptomycin. The invasion assay was conducted as described (15).…”

Section: Cell-inverted Invasion Assaymentioning

confidence: 99%

High-Risk Endometrial Carcinoma Profiling Identifies TGF-β1 as a Key Factor in the Initiation of Tumor Invasion

Muinelo‐Romay

Colás

Barbazán

et al. 2011

Molecular Cancer Therapeutics

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Endometrial cancer is among the three most common cancers in females in industrialized countries. In the majority of cases, the tumor is confined to the uterus at the time of diagnosis and presents a good prognosis. However, after primary surgery, 15% to 20% of these tumors recur and have limited response to systemic therapy. We carried out gene expression profiling of high-risk recurrence endometrial cancers to identify new therapeutic approaches targeting the molecular pathways involved in the acquisition of an aggressive tumor phenotype. A microarray gene-expression analysis on a total of 51 human endometrial carcinomas revealed 77 genes specifically altered in high-risk recurrence tumors (P < 0.001). The bioinformatics analysis of gene-gene interactions and molecular relationships among these genes pointed to a prominent role for TGFb1 signaling in the acquisition of an aggressive phenotype. We further showed that TGF-b1 has a principal role at the initiation of endometrial carcinoma invasion through the promotion of the epithelial to mesenchymal transition that leads to the acquisition of an invasive phenotype in HEC-1A and RL95-2 cells. Impairment of this initial step with SB-431542, a specific TGF-b1 inhibitor, precluded further persistent endometrial carcinoma invasion. In conclusion, we showed that the characterization of the molecular changes associated with the acquisition of an aggressive phenotype represents a realistic strategy for the rational identification and characterization of new potential therapeutic targets in an effort to improve the clinical management and the outcome of high-risk endometrial cancer patients. Mol Cancer Ther; 10(8); 1357-66. '2011 AACR.

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“…30,31 Moreover, Erm overexpression enhances the aggressiveness of cancer cells in vitro and correlates with disease progression in endometrial carcinoma. [32][33][34] To the best of our knowledge, the roles of Pea3 group transcription factors in ESCC have not been studied. In the present study, we investigated the expression of the three transcription factors in an ESCC patient cohort and found that Pea3 overexpression was associated with poor prognosis.…”

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The Role of Pea3 Group Transcription Factors in Esophageal Squamous Cell Carcinoma

Yuen

McCrudden

Chan

et al. 2011

The American Journal of Pathology

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The transcription factors Pea3, Erm, and Er81 can promote cancer initiation and progression in various types of solid tumors. However, their role in esophageal squamous cell carcinoma (ESCC) has not been elucidated. In this study, we found that the expression levels of Pea3 and Erm, but not that of Er81, were significantly higher in ESCC compared with nontumor esophageal epithelium. A high level of Pea3 expression was significantly correlated with a shorter overall survival in a cohort of 81 patients with ESCC and the subgroup with N1 stage tumor (WilcoxonGehan test, P ‫؍‬ 0.016 and P ‫؍‬ 0.001, respectively). Pea3 was overexpressed in seven ESCC cell lines compared with two immortalized esophageal cell lines. Pea3 knockdown reduced cell proliferation and suppressed nonadherent growth, migration, and invasion in ESCC cells in vitro. In addition, Pea3 knockdown in ESCC cells resulted in a down-regulation of phospho-Akt and matrix metalloproteinase 13, whereas a significant positive correlation in the expression levels was observed between Pea3 and phospho-Akt (r ‫؍‬ 0.281, P < 0.013) and between Pea3 and matrix metalloproteinase 13 in the human specimens (r ‫؍‬ 0.462, P < 0.001). Moreover, Pea3 modulated the sensitivity of EC109 cells to doxorubicin, probably via reduced activity of the phosphatidylinositol 3-kinase-Akt-mammalian target of Rapamycin complex 1 pathway on Pea3 knockdown. In conclusion, our results suggest that Pea3 plays an important role in the progression of ESCC. Esophageal squamous cell carcinoma (ESCC) is common among Asian populations. 1 Despite recent advances in the detection of the premalignant lesions and the development of combination therapies, its incidence is increasing, and its outcome remains poor. [2][3][4] Given the poor prognosis of ESCC and its high incidence rate, it is increasingly important to understand the initiation and progression of this type of cancer and to identify the associated prognostic factors.Pea3, Erm, and Er81 belong to the Pea3 subgroup of the Ets transcription factor family. This group of proteins contains several functional domains, and the individual members demonstrate extensive amino acid sequence similarities. 5 The roles of these proteins in mammary gland development and tumorigenesis have also been extensively studied and reviewed. 6 -8 Pea3 group transcription factors promote metastatic development and cancer progression through transcriptional activation of metastasis-related genes, such as matrix metalloproteinases (MMPs) 9 -13 and cyclooxygenase (COX)-2. 14,15 Overexpression of Pea3 also increases the motility and invasiveness of lung cancer cells via activation of the pathway and an increase in COX-2 expression. 16 -18 The prognostic significance of Pea3 has also been demonstrated in various solid tumors. Pea3 is overexpressed in mouse metastatic mammary adenocarcinoma 19 and in human breast cancer, in which its overexpression is also correlated with HER-2 expression and poor prognosis. 20 -23

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ERM/ETV5 Up-regulation Plays a Role during Myometrial Infiltration through Matrix Metalloproteinase-2 Activation in Endometrial Cancer

Cited by 55 publications

References 28 publications

An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis

An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis

High-Risk Endometrial Carcinoma Profiling Identifies TGF-β1 as a Key Factor in the Initiation of Tumor Invasion

The Role of Pea3 Group Transcription Factors in Esophageal Squamous Cell Carcinoma

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