Mutually exclusive mutations of the Pten and ras pathways in skin tumor progression
Mutually exclusive mutations of the Pten and ras pathways in skin tumor progression
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DOI：
10.1101/gad.1213804
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发表时间：
2004-08-01
影响因子：
10.5
通讯作者：
Balmain, A
中科院分区：
文献类型：
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作者：
Mao, JH;To, MD;Balmain, A
与对照组相比，PTEN杂合子(Pten(+/-))小鼠在使用二甲基苯并(DMBA)和十四酰佛波醇醋酸酯(TPA)进行皮肤治疗后，乳头状瘤数量增加，癌症潜伏期缩短。H-ras突变通常是DMBA-TPA诱导的皮肤肿瘤的标志，但来自Pten(+/-)小鼠的70%的癌症没有表现出这种突变，并且在所有情况下都失去了野生型Pten等位基因。保留Pten野生型等位基因的肿瘤也有H-ras突变，这表明在皮肤癌中H-ras激活和Pten完全缺失是相互排斥的事件。丝裂原活化蛋白激酶(MAPK)在H-ras突变的肿瘤中持续激活，但在Pten(-/-)肿瘤中表达强烈下调，提示这一途径在皮肤癌的形成中是必不可少的。这些数据对设计癌症治疗的个体化治疗策略具有重要意义。
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.