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.
University of California at San Francisco Comprehensive Cancer Center, San Francisco, California 94143, USA.
Jian-Hua
JH
Mao
Minh D
MD
To
Jesus
J
Perez-Losada
Di
D
Wu
Reyno
R
Del Rosario
Allan
A
Balmain
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