Src kinase induces tumor formation in the c-SRC C57BL/6 mouse.
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 p21-/- 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.
Kline
Christina Leah B
CL
Penn State Cancer Institute H072, Penn State College of Medicine, 500 University Drive, PO 850, Hershey, PA 17033, USA.
Jackson
Rosalind
R
Engelman
Robert
R
Pledger
Warren Jack
WJ
Yeatman
Timothy J
TJ
Irby
Rosalyn B
RB
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D006801:Humans; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019061:src-Family Kinases / Q000378:metabolism*
D017931:DNA Primers; D008668:Metallothionein; D019061:src-Family Kinases