Role of SRC kinases in Neu-induced tumorigenesis: challenging the paradigm using Csk homologous kinase transgenic mice.
Amplification of the HER-2/neu (ErbB2) gene is observed in approximately 30% of human breast cancers, correlating with a poor clinical prognosis. Src kinases are also involved in the etiology of breast cancer, and their activation was suggested to be necessary for Neu-induced oncogenesis. To address whether Src activity is essential for Neu-mediated tumorigenesis, we used a physiologic inhibitor of Src kinase activity, the Csk homologous kinase (CHK), expressed as a mammary tissue-specific transgene. Our data, using a physiologic inhibitor of Src activity (CHK), showed that blocking of Neu-induced Src activity without altering Src expression levels had no significant effects on Neu-mediated mammary tumorigenesis in vivo. This contradicts the current paradigm that activation of Src kinases is essential for Neu-induced oncogenesis. This study is the first to distinguish between the kinase-dependent and kinase-independent actions of Src and shows that its kinase-dependent properties are not requisite for Neu-induced tumorigenesis.
Kaminski
Rafal
R
Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Wellman Laboratory of Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Zagozdzon
Radoslaw
R
Fu
Yigong
Y
Mroz
Pawel
P
Fu
Wei
W
Seng
Seyha
S
Avraham
Shalom
S
Avraham
Hava Karsenty
HK
D000818:Animals; D005260:Female; D018734:Genes, erbB-2 / Q000502:physiology; D008321:Mammary Glands, Animal / Q000201:enzymology* / Q000254:growth & development; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D019061:src-Family Kinases