Abstract 1229: The oncogenic aspects of deregulated Stat5 activity in the mammary gland

Abstract Stat5 is a latent transcription factor, regulating growth and survival functions in normal cells. Deregulated Stat5 activity has been implicated in blood cell malignancies and mammary / breast cancer. We studied Stat5 oncogenic role in transgenic mice overexpressing its native, constitutively active (STAT5ca) and C-terminally truncated (STAT5Δ750) forms in the mammary gland and in culture. Overexpression and forced activation of the oStat5 (homologous to the mStat5a) cause parity-dependent formation of differentiated papillary or micropapillary tumors in the mammary gland of postestrapusal transgenic mice. In contrast, expression of its truncated form, mainly initiates the poorly differentiated carcinomas. Array analyses distinct tumors caused by STAT5ca and the STAT5Δ750. 50 genes were specifically affected by STAT5ca, and 94% of these were downregulated, the latter involved in suppression of tumor suppressors and proliferation antagonistics. This substantial downregulation distinguishes the STAT5ca-induced tumorigenic consequences from the relatively equal effect of the STAT5Δ750 on gene expression, which included significant elevation in the expression of oncogenes and growth mediators. The different gene-expression profiles in mammary tumors caused by the STAT5Δ750 and STAT5ca variants, corroborated by the absence of a direct link to transgenic STAT5 expression, imply distinct metabolic consequences for their oncogenic role. Gene expression profile was also compared between the resulting papillary adenocarcinomas and the poorly differentiated carcinomas. At least six metabolic pathways support the morphological and functional differences between these tumors. In the carcinoma, stronger expression of genes coding for specific integrins, cytoskeletal proteins and calcium-binding proteins highlight cell-adhesion and motility features of the tumor cells. This is supported by the higher expression of genes involved in O-glycan synthesis, TGF-β pathway, as well as the Notch ligands and members of the γ-secretase complex that enable Notch nuclear localization. The Wnt pathway was also a target for differential gene expression which resulted in membranal accumulation of β-catenin in the papillary tumors, in contrast to its nuclear translocation in the carcinoma. Genes involved in cell-cycle arrest at G1 and response to DNA damage were more highly expressed in the papillary adenocarcinomas, as opposed to favored G2/M regulation in the carcinoma tumors. In culture, transfected CID-9 cells with STAT5ca, accumulated DNA damage within 3 days after the addition of lactogenic hormones. Significant induction in the expression of Chk2, H2A.X. Brca1, p53 and c-Myc was noted. Surprisingly, no sign for cell senescence was observed. We propose that mutation accumulated in damaged cells surviving the repeated reproduction cycles may participate in the oncogenic effect of Stat5 that is observed in aged females. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 1229.