Prognostic Value of <b>
                     <i>ERM</i>
                  </b> Gene Expression in Human Primary Breast Cancers

Chotteau-Lelièvre, Anne; Révillion, Françoise; Lhotellier, V.; Hornez, Louis; Desbiens, Xavier; Cabaret, Véronique; Launoit, Yvan de; Peyrat, Jean‐Philippe

doi:10.1158/1078-0432.ccr-04-0593

Cited by 39 publications

(34 citation statements)

References 35 publications

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“…Recent data confirmed the role of Pea3 in breast cancer tumorigenesis and suggest that Pea3 is a marker of tumor aggressiveness rather than a prognostic factor (26). Moreover, we have shown that Erm expression is an adverse prognostic factor for overall survival in breast cancer patients (27).…”

supporting

confidence: 71%

Pea3 Transcription Factor Cooperates with USF-1 in Regulation of the Murine bax Transcription without Binding to an Ets-binding Site

Firlej

Bocquet

Desbiens

et al. 2005

Journal of Biological Chemistry

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The Pea3 transcription factor (which belongs to the PEA3 group) from the Ets family has been shown to be involved in mammary embryogenesis and oncogenesis. However, except for proteinases, only few of its target genes have been reported. In the present report, we identified bax as a Pea3 up-regulated gene. We provide evidence of this regulation by using Pea3 overexpression and Pea3 silencing in a mammary cell line. Both Pea3 and Erm, another member of the PEA3 group, are able to transactivate bax promoter fragments. Although the minimal Pea3-regulated bax promoter does not contain an Ets-binding site, two functional upstream stimulatory factor-regulated E boxes are present. We further demonstrate the ability of Pea3 and USF-1 to cooperate for the transactivation of the bax promoter, mutation of the E boxes dramatically reducing the Pea3 transactivation potential. Although Pea3 did not directly bind to the minimal bax promoter, we provide evidence that USF-1 could form a ternary complex with Pea3 and DNA. Taken together, our results suggest that Pea3 may regulate bax transcription via the interaction with USF-1 but without binding to DNA.Pea3, also called E1AF or ETV4, is the founding member of a subfamily of ets genes that includes Er81 (or ETV1) and Erm (or ETV5), which have been currently characterized in mice (1-3), humans (4 -6), rats, dogs (Telgman, GenBank TM accession number AJ313194), chicken (7), zebrafish (8), and amphibian Xenopus (9). These three factors share three functional highly conserved domains: a DNA binding domain (10), an amino-terminal transactivation domain (11), and a carboxylterminal domain involved in DNA binding and transactivation regulation (12, 13).These three PEA3 group members are co-expressed in several tissues and organs (3, 14, 15) and are generally described as transactivators (11,16). Their role and function are not precisely known, but deregulation of their expression is often associated with carcinogenesis (17, 18).Numerous studies (11, 16 -24) have revealed the involvement of the three factors in mammary oncogenesis, since their overexpression is observed in certain human breast cancers and in oncogene-induced mammary tumors. Pea3 ectopic overexpression in nonmetastatic human breast cancer cells increased their invasiveness and their metastatic potential in nude mice (25). Recent data confirmed the role of Pea3 in breast cancer tumorigenesis and suggest that Pea3 is a marker of tumor aggressiveness rather than a prognostic factor (26). Moreover, we have shown that Erm expression is an adverse prognostic factor for overall survival in breast cancer patients (27).The PEA3 group members are also expressed in different stages of normal mammary gland development, from embryonic emergence to post-natal evolution (3,14,15), with a high level during extensive ductal outgrowth and branching, i.e. puberty and early pregnancy. Moreover, overexpression of Erm and Pea3 in a normal mouse mammary cell line confers an autonomous capacity of branching morphogenesis (15), thus supporting ...

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confidence: 71%

Pea3 Transcription Factor Cooperates with USF-1 in Regulation of the Murine bax Transcription without Binding to an Ets-binding Site

Firlej

Bocquet

Desbiens

et al. 2005

Journal of Biological Chemistry

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“…Correlation between the expression of the tyrosine kinase receptor Her2 and Pea3 has also been shown, since this latter is expressed in the majority of tumors expressing Her2 (Benz et al, 1997;Fleming et al, 2004). Expression of another PEA3 group member, Erm, is detectable in more than 80% of human breast cancers, thus also demonstrating a role of this transcription factor in breast cancer and, more particularly, as an independent adverse prognosis factor for overall survival (Chotteau-Lelievre et al, 2004). In experimental mammary models, it has been demonstrated that ectopic overexpression of Pea3 in non-metastatic human breast-cancer cells increases their invasiveness and their metastasis potential in nude mice (Kaya et al, 1996).…”

Section: Introductionmentioning

confidence: 89%

Reduced tumorigenesis in mouse mammary cancer cells following inhibition of Pea3- or Erm-dependent transcription

Firlej

Ladam

Brysbaert

et al. 2008

Journal of Cell Science

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Pea3 and Erm are transcription factors expressed in normal developing branching organs such as the mammary gland. Deregulation of their expression is generally associated with tumorigenesis and particularly breast cancer. By using RNA interference (RNAi) to downregulate the expression of Pea3 and/or Erm in a mammary cancer cell line, we present evidence for a role of these factors in proliferation, migration and invasion capacity of cancer cells. We have used different small interfering RNAs (siRNAs) targeting pea3 and erm transcripts in transiently or stably transfected cells, and assessed the physiological behavior of these cells in in vitro assays. We also identified an in vivo alteration of tumor progression after injection of cells that overexpress pea3 and/or erm short hairpin RNAs (shRNAs) in immunodeficient mice. Using transcriptome profiling in Pea3- or Erm-targeted cells, two largely independent gene expression programs were identified on the basis of their shared phenotypic modifications. A statistically highly significant part of both sets of target genes had previously been already associated with the cellular signaling pathways of the `proliferation, migration, invasion' class. These data provide the first evidence, by using endogenous knockdown, for pivotal and complementary roles of Pea3 and Erm transcription factors in events crucial to mammary tumorigenesis, and identify sets of downstream target genes whose expression during tumorigenesis is regulated by these transcription factors.

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“…Cdx2 and GCC mRNA and protein expression in tumors and matched normal mucosal specimens were compared using the Wilcoxon signed-rank test (27). Correlation of Cdx2 with GCC expression was quantified by the Spearman correlation coefficient, a nonparametric estimate (28). Cdx2 transcriptional activity in tumors and matched normal mucosal specimens were compared using the Student's t test.…”

Section: Methodsmentioning

confidence: 99%

The Putative Tumor Suppressor Cdx2 Is Overexpressed by Human Colorectal Adenocarcinomas

Witek

Nielsen

Walters

et al. 2005

Clinical Cancer Research

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Purpose:The current paradigm suggests that the homeodomain transcription factor Cdx2, which directs the development and maintenance of the intestinal epithelium, is a tumor suppressor in the colon and rectum. Although a cardinal property of tumor suppressors is their inactivation during carcinogenesis, the expression of Cdx2 in colorectal tumors has not been compared with that in normal mucosa. Here, Cdx2 expression and function was quantified in tumors and matched normal mucosa from patients with colorectal cancer. Experimental Design: Cdx2 expression was quantified by reverse transcription-PCR, immunoblot analysis, and immunohistochemistry. Transcriptional activity was explored by quantifying expression of an endogenous downstream target of Cdx2, guanylyl cyclase C (GCC), in tissues by quantitative reverse transcription-PCR and expression of exogenous Cdx2-specific luciferase promoter constructs in epithelial cells isolated from tumors and normal mucosa. Results: Most (>80%) colorectal tumors overexpressed Cdx2 mRNA and protein compared with normal mucosa, with median fold increases of 3.6 and 1.4, respectively (P < 0.002). Concomitantly, immunohistochemistry revealed elevated levels of Cdx2 in nuclei of tumor cells compared with normal epithelial cells. Further, tumors exhibited increased expression of GCC compared with normal mucosa. Moreover, cells isolated from tumors overexpressed a Cdx2-specific luciferase promoter construct compared with normal mucosal cells. Conclusion:These observations show, for the first time, the structural and functional overexpression of Cdx2 by human colorectal tumors compared with matched normal mucosa. They suggest that loss of Cdx2 expression or transcriptional activity is an infrequent event during tumorigenesis, which does not contribute to molecular mechanisms underlying initiation and progression of most colorectal tumors.

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Prognostic Value of ERM Gene Expression in Human Primary Breast Cancers

Cited by 39 publications

References 35 publications

Pea3 Transcription Factor Cooperates with USF-1 in Regulation of the Murine bax Transcription without Binding to an Ets-binding Site

Pea3 Transcription Factor Cooperates with USF-1 in Regulation of the Murine bax Transcription without Binding to an Ets-binding Site

Reduced tumorigenesis in mouse mammary cancer cells following inhibition of Pea3- or Erm-dependent transcription

The Putative Tumor Suppressor Cdx2 Is Overexpressed by Human Colorectal Adenocarcinomas

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