Mutually exclusive mutations of the Pten and ras pathways in skin tumor progression.
Pten heterozygous (Pten+/-) mice develop increased papilloma numbers and show decreased carcinoma latency time in comparison with controls after skin treatment with dimethyl benzanthracene (DMBA) and tetradecanoyl-phorbol acetate (TPA). H-ras mutation is normally a hallmark of DMBA-TPA-induced skin tumors, but 70% of carcinomas from Pten+/- mice do not exhibit this mutation, and in all cases have lost the wild-type Pten allele. Tumors that retain the Pten wild-type allele also have H-ras mutations, indicating that activation of H-ras and complete loss of Pten are mutually exclusive events in skin carcinomas. Mitogen-activated protein kinase (MAPK) is consistently activated in the tumors with H-ras mutations, but is strongly down-regulated in Pten-/- tumors, suggesting that this pathway is dispensable for skin carcinoma formation. These data have important implications in designing individual therapeutic strategies for the treatment of cancer.
Mao
Jian-Hua
JH
University of California at San Francisco Comprehensive Cancer Center, San Francisco, California 94143, USA.
To
Minh D
MD
Perez-Losada
Jesus
J
Wu
Di
D
Del Rosario
Reyno
R
Balmain
Allan
A
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D018450:Disease Progression; D011905:Genes, ras / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D051059:PTEN Phosphohydrolase; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D025521:Tumor Suppressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D013755:Tetradecanoylphorbol Acetate