Abstract
BackgroundEts transcription factors have been widely implicated in the control of tumorigenesis, with most studies suggesting tumor-promoting roles. However, few studies have examined Ets tumorigenesis-modifying functions in vivo using model genetic systems.MethodsUsing mice expressing a previously characterized Ets dominant repressor transgene in the intestinal epithelium (Villin-En/Erm), we examined the consequences of blocking endogenous Ets-mediated transcriptional activation on tumorigenesis in the ApcMin model of intestinal carcinoma.ResultsEn/Erm expression in the intestine, at levels not associated with overt crypt-villus dysmorphogenesis, results in a marked increase in tumor number in ApcMin animals. Moreover, when examined histologically, tumors from En/Erm-expressing animals show a trend toward greater stromal invasiveness. Detailed analysis of crypt-villus homeostasis in these En/Erm transgenic animals suggests increased epithelial turnover as one possible mechanism for the enhanced tumorigenesis.ConclusionOur findings provide in vivo evidence for a tumor-restricting function of endogenous Ets factors in the intestinal epithelium.
Highlights
Ets transcription factors have been widely implicated in the control of tumorigenesis, with most studies suggesting tumor-promoting roles
Ets factors are widely expressed in the intestine, and often misexpressed in carcinoma of the colon, but their tumor-modifying roles in intestinal epithelial neoplasia in vivo largely remain to be defined [9]
We established additional lines, which stably integrated the Villin-En/ Erm transgene, but did not express En/Erm at immunohistochemically detectable levels. Animals from such lines did not manifest an overt disturbance of crypt-villus homeostasis (Figure 1A), indicating a threshold level of transgene expression for the previously described dramatic dysmorphogenesis phenotype [10]
Summary
Ets transcription factors have been widely implicated in the control of tumorigenesis, with most studies suggesting tumor-promoting roles. Few studies have examined Ets tumorigenesis-modifying functions in vivo using model genetic systems. Members of the Ets transcription family, numbering up to 27 in humans, are widely expressed in developing and mature tissues, and regulate diverse cellular processes [1,2]. Ets factors are frequently misexpressed in the setting of neoplasia. Very few studies have examined Ets functions in tumorigenesis in vivo using model genetic systems [6,7,8]. Ets factors are widely expressed in the intestine, and often misexpressed in carcinoma of the colon, but their tumor-modifying roles in intestinal epithelial neoplasia in vivo largely remain to be defined [9]
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