Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten
Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten
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DOI：
10.1073/pnas.0308217100
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发表时间：
2004-02-10
影响因子：
11.1
通讯作者：
Mak, TW
中科院分区：
文献类型：
--
作者：
Backman, SA;Ghazarian, D;Mak, TW
PTEN是一种肿瘤抑制基因，在多种晚期人类肿瘤中发生突变，包括胶质母细胞瘤和前列腺癌、乳腺癌、子宫内膜癌和肾癌。这种肿瘤抑制因子是一种脂质磷酸酶，通过磷脂酰肌醇3-激酶/蛋白激酶B信号转导负向调节细胞的存活和增殖。使用Cre-IoxP系统，我们选择性地灭活了MMTV-LTR启动子激活的小鼠组织中的Pten，导致Pten缺失的皮肤和前列腺的过度增殖和肿瘤性变化。这些表型起病早，而且是完全渗透性的。Pten突变皮肤的异常包括轻度表皮增生，而这些小鼠的前列腺表现为高度前列腺上皮内瘤变(HGPIN)，经常进展为局灶性浸润性癌症。这些数据表明，Pten是皮肤和前列腺生长的重要生理调节因子。此外，在Pten突变的男性中，HGPIN的早期发病是该动物模型所特有的，并表明PTEN突变与前列腺癌的发生有关。这些数据与人类前列腺癌中PTEN的高突变率一致，表明PTEN在该器官中是一个关键的肿瘤抑制因子。
PTEN is a tumor suppressor gene mutated in various advanced human neoplasias, including glioblastomas and prostate, breast, endometrial, and kidney cancers. This tumor suppressor is a lipid phosphatase that negatively regulates cell survival and proliferation mediated by phosphatidylinositol 3-kinase/protein kinase B signaling. Using the Cre-IoxP system, we selectively inactivated Pten in murine tissues in which the MMTV-LTR promoter is active, resulting in hyperproliferation and neoplastic changes in Pten-null skin and prostate. These phenotypes had early onset and were completely penetrant. Abnormalities in Pten mutant skin consisted of mild epidermal hyperplasia, whereas prostates from these mice exhibited high-grade prostatic intraepithelial neoplasia (HGPIN) that frequently progressed to focally invasive cancer. These data demonstrate that Pten is an important physiological regulator of growth in the skin and prostate. Further, the early onset of HGPIN in Pten mutant males is unique to this animal model and implicates PTEN mutations in the initiation of prostate cancer. Consistent with high PTEN mutation rates in human prostate tumors, these data indicate that PTEN is a critical tumor suppressor in this organ.