Id1 cooperates with oncogenic Ras to induce metastatic mammary carcinoma by subversion of the cellular senescence response.
Recent evidence demonstrates that senescence acts as a barrier to tumorigenesis in response to oncogene activation. Using a mouse model of breast cancer, we tested the importance of the senescence response in solid cancer and identified genetic pathways regulating this response. Mammary expression of activated Ras led to the formation of senescent cellular foci in a majority of mice. Deletion of the p19(ARF), p53, or p21(WAF1) tumor suppressors but not p16(INK4a) prevented senescence and permitted tumorigenesis. Id1 has been implicated in the control of senescence in vitro, and elevated expression of Id1 is found in a number of solid cancers, so we tested whether overexpression of Id1 regulates senescence in vivo. Although overexpression of Id1 in the mammary epithelium was not sufficient for tumorigenesis, mice with expression of both Id1 and activated Ras developed metastatic cancer. These tumors expressed high levels of p19(Arf), p53, and p21(Waf1), demonstrating that Id1 acts to make cells refractory to p21(Waf1)-dependent cell cycle arrest. Inactivation of the conditional Id1 allele in established tumors led to widespread senescence within 10 days, tumor growth arrest, and tumor regression in 40% of mice. Mice in which Id1 expression was inactivated also exhibited greatly reduced pulmonary metastatic load. These data demonstrate that established tumors remain sensitive to senescence and that Id1 may be a valuable target for therapy.
Swarbrick
Alexander
A
Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia. a.swarbrick@garvan.org.au
Roy
Emie
E
Allen
Thaddeus
T
Bishop
J Michael
JM
D000818:Animals; D017690:Cell Transplantation; D002478:Cells, Cultured; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004847:Epithelial Cells; D005260:Female; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000502:physiology*; D008321:Mammary Glands, Animal; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins / Q000502:physiology*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins