Abstract 1241: Tcf7, a mediator of Wnt/β-catenin signaling, is upregulated in mammary glands of BK5.ATF3 mice, without prior development of mammary tumors

Abstract

We previously showed that in a transgenic model (BK5.ATF3) in which the transcription factor ATF3 is overexpressed in cytokeratin 5 (CK5)-expressing cells, parous female mice develop mammary carcinomas with about 70% incidence between 6 months and one year of age. In these mice, ATF3 is overexpressed in cell nuclei in the myoepithelial cell layer (basal layer) of normal mammary glands, and in the basal cell layers of the tumors, in addition to expression in epidermis and other CK5-expressing epithelia. Non-parous, female transgenic mice exhibited a high incidence of squamous metaplastic lesions in the mammary glands between 14 and 32 weeks of age. These lesions showed dysregulation of cytokeratin expression, but no other molecular defects in non-parous mammary glands have been described. Several genes in the EGFR-MAPK pathway and in the Wnt/β-catenin pathway are misregulated in the mammary tumors that arise in parous transgenic mice. When expression of these genes was compared between normal mammary glands from transgenic and non-transgenic mice, the only genes that showed significant differences were Lef1 and Tcf7, two members of the family of transcription factors that dimerize with β-catenin to mediate Wnt-induced transcription. These genes were overexpressed by 2.5-3-fold in the transgenic mammary glands. A mouse mammary tumor cell line, EMT6, was found to have high levels of expression of both Atf3 and Tcf7, but not Lef1. Expression of Atf3 was knocked down by 97% in EMT6 cells 48 hrs post-treatment with Atf3-specific siRNA. This resulted in about a 70% decrease in expression of Tcf7, and a similar decrease in expression of cJun, a known target of Wnt/β-catenin signaling. This is consistent with the possibility that Tcf7 is a target gene for Atf3, and may be involved in the early stages of tumorigenesis in this model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1241.