Abstract LB-68: Mouse mammary tumor virus suppress apoptosis through Src signaling in the mammary epithelial cells

Abstract

Abstract Many receptors in the hematopoietic immune cells use common signaling pathway that relies on immunoreceptor tyrosine-based activation motif (ITAM). ITAMs are highly conserved sequence. Signal transduction by these motifs is mediated by Src family tyrosine kinases including Lyn, Fyn, Lck. ITAM bearing proteins are found in many oncogenic viruses and associated with transformation and tumorigenesis in epithelial and endothelial cells. These proteins include Epstein Barr Virus LMP2A, Kaposi's sarcoma virus K1, and bovine leukemia virus gp30. MMTV envelope protein is another viral ITAM bearing protein implicated in mammary tumor development. We previously have shown that MMTV envelope protein expression transform mouse mammary epithelial cells and Src kinases are important mediators in this transformation. To study how ITAM signaling affects transformation and progression of mammary tumor we developed mammary cell lines that express MMTV provirus and have a mutated ITAM counterpart. Using PCR based expression profiling we found that MMTV-ITAM turns on the embryonic transcription factors and induce epithelial-mesenchymal transition which is important in malignant tumor progression. Many genes related to cell adhesion and invasion was changed. Anti-apoptotic regulator bcl-2 level was significantly increased. Importantly MMTV expressing cells became resistant to apoptosis induced by serum starvation. Cells transduced with ITAM mutated MMTV were indistinguishable from wild type cells. We also found Src kinase, a downstream signal transducer of ITAM signaling is activated in the MMTV expressing cells, and MMTV induced apoptosis resistance was completely restored by Src inhibitor PP2. Our results show that MMTV suppress apoptosis through ITAM mediated Src tyrosin kinase signaling. The studies in signaling pathways and apoptosis resistance induced by ITAM containing proteins in nonhematopoietic cells could lead to the development of effective treatment of cancers in which ITAM-mediated signaling plays a role. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-68. doi:1538-7445.AM2012-LB-68