Abstract A44: Src-induced human cell transformation

Abstract

Abstract Src is one of the oldest and most investigated oncogenes, and its family members make up the largest group of non-recepter tyrosine kinases. The elevated Src expression and kinase activity have been seen in multiple solid tumors including colon and breast cancer, and many in vitro experiments have shown a critical role of Src in cellular growth and proliferation, angiogenesis, and invasion and metastasis. However, there is no obvious mutation of Src has been linked with the development of human cancer unlike activating mutations of Ras were often found in various types of human cancer, and therefore direct involvement of Src in human cancer pathogenesis has still remained obscure. In order to directly assess the oncogenic potential of Src in human cells, we have expressed activated Src (v-Src) in human diploid fibroblasts (HDF) which were immortalized by the combination of human telomerase reverse transcriptase (hTERT) and SV40 early region (ER). These v-src-expressing HDF exhibit more drastic morphological changes, aggressive tumorigenecity in nude mice, and higher activity of both MAPK and PI3K signaling pathways when compared to the equivalent HDF transformed by H-ras V12. Curiously, there is no such difference between v-Src and H-ras V12 in the transformation of rodent fibroblasts. Such highly tumorigenic potential of v-Src is not limited to fibroblasts, and we have succeeded to transform normal human mammary epithelial cells (HMEC) into aggressive tumor cells by the similar procedure as in HDF. These v-Src transformed HMEC should provide a useful model cell system for understanding the molecular basis of some types of human breast cancer. Citation Information: Cancer Res 2009;69(23 Suppl):A44.