Src kinase induces tumor formation in the c‐SRC C57BL/6 mouse

Abstract

Src kinase has been linked as a causative agent in the progression of a number of cancers including colon, breast, lung and melanoma. Src protein and activity levels are increased in colorectal cancer and liver metastases arising secondary to colon cancer. However, although Src protein is increased in colon cancer as early as the adenomatous polyp stage, a role for Src in carcinogenesis has not been established. We developed the c-SRC transgenic mouse in the C57BL/6 strain to address the issue of carcinogenesis in cells with high levels of Src expression. The transgene was constructed with the human c-SRC gene downstream of the mouse metallothionein promoter to create zinc inducible gene expression. In these C57BL/6 mice, Src protein was increased in a number of tissues both with and without zinc induction. No additional carcinogenic agent was administered. After 20 months, mice were assessed for tumor development in the liver and GI tract, as well as other organs. Of the mice with the transgene, 15% developed tumors in the liver while no tumors were detected in wild type C57BL/6 mice. A further study was conducted by crossing c-SRC C57BL/6 mice with p21 nullizygous mice to determine the effect of oncogene expression combined with inactivation of the tumor suppressor gene, p21. Addition of the c-SRC transgene to the p212/2 background increased tumor formation almost 3-fold, while it increased metastasis 6-fold. The data from our study show, for the first time, that Src kinase may play a role in carcinogenesis. ' 2008 Wiley-Liss, Inc.Key words: Src; transgenic mice; p21; carcinogenesis; metastasis Src is a nonreceptor tyrosine kinase that induces signal transduction in multiple pathways regulating cellular behavior. 1-3 Previous studies have shown that Src kinase activity is elevated in a variety of human cancers, 4-8 and has been linked with the progression and metastasis of cancer in humans. However, the exact role of Src in these processes remains elusive. 9-11 Src has been the focus of a number of studies using cultured cells, human tissues, and nude mouse experiments. [11][12][13][14][15][16] Src activity was shown to be important for tumor formation and metastasis in mouse models of prostate, ovarian and colon tumors, often through VEGF, Akt and Erk pathways. [17][18][19][20] Fibroblasts transfected with activated Src show a transformed phenotype when used in soft agar assays and in nude mouse models of metastasis. 21 Src has been shown to increase migration and invasion of human colon cancer cells in vitro. [22][23][24][25] The increase in invasion may be a result of a variety of events including altered activity of adhesion proteins, integrins and cadherins 26,27 and altered secretion of proteinases into the extracellular matrix. 28 However, while Src levels are increased during the progression of colorectal cancer as early as adenomatous polyps, there is little proof that Src initiates tumor development. To study the tumorigenicity of the Src protein, we developed a c-SRC C57BL/6 mouse model.Mouse model...

Missing-in-Metastasis regulates cell motility and invasion via PTPδ-mediated changes in SRC activity

“…Overexpression of SRC is observed in many cancers, including breast cancer [47]; however, overexpression or hyperactivation of SRC in transgenic mouse models is not sufficient to induce a higher grade of breast tumor and metastasis [48]. In contrast, transgenic overexpression of SRC in a p21−/− background dramatically induces tumor growth and metastasis, suggesting that the combination with a second hit may augment the transforming activity of SRC [49]. Considering the positive effect of PTPδ on SRC activity, loss of MIM may promote tumor growth and metastasis particularly in breast tumors in which SRC is overexpressed.…”

Identification of PTPN23 as a novel regulator of cell invasion in mammary epithelial cells from a loss-of-function screen of the ‘PTP-ome'

“…However, it has been shown in transgenic mouse models that overexpression or hyperactivation of SRC is not sufficient to induce a higher-grade breast tumor and its metastasis (Webster et al 1995). Interestingly, transgenic overexpression of SRC in a p21 À/À background dramatically induces tumor growth and metastasis (Kline et al 2008), suggesting that the inactivation of tumor suppressors augments SRC transforming activity. Considering the negative effect of PTPN23 on SRC activity, loss of PTPN23 may promote tumor growth and metastasis in breast tumors for which SRC is overexpressed.…”

Cullin5 destabilizes Cas to inhibit Src-dependent cell transformation

“…Cas phosphorylation by Src stimulates cancer cell invasion and also stimulates Akt, the anti-apoptotic pathway, growth factorindependence and, in breast cancer, induces resistance to antiestrogens (Bouton et al, 2001;Cabodi et al, 2006;Schrecengost et al, 2007;Stupack et al, 2000;Tornillo et al, 2011;van der Flier et al, 2000). Because Src is highly active in many human tumors but is only weakly oncogenic in mice (Kline et al, 2008;Summy and Gallick, 2003), decreased expression of CUL5 and SOCS genes might contribute to some aspects of cancer progression by activating tyrosine phosphorylation of proteins such as Cas.…”