Backman Stéphanie A, Ghazarian Danny, So Kelvin, Sanchez Otto, Wagner Kay-Uwe, Hennighausen Lothar, Suzuki Akira, Tsao Ming-Sound, Chapman William B, Stambolic Vuk, Mak Tak W
Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute and University Health Network, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9.
Proc Natl Acad Sci U S A. 2004 Feb 10;101(6):1725-30. doi: 10.1073/pnas.0308217100. Epub 2004 Jan 27.
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-loxP 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.
PTEN是一种肿瘤抑制基因，在多种晚期人类肿瘤中发生突变，包括胶质母细胞瘤以及前列腺癌、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，它对由磷脂酰肌醇3激酶/蛋白激酶B信号介导的细胞存活和增殖起负调节作用。利用Cre-loxP系统，我们在MMTV-LTR启动子活跃的小鼠组织中选择性地使Pten失活，导致Pten基因缺失的皮肤和前列腺出现过度增殖和肿瘤性变化。这些表型发病早且完全显现。Pten突变皮肤的异常表现为轻度表皮增生，而这些小鼠的前列腺则表现出高级别前列腺上皮内瘤变（HGPIN），且常常进展为局灶性浸润癌。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，Pten突变雄性小鼠中HGPIN的早发是该动物模型所特有的，提示PTEN突变与前列腺癌的起始有关。与人类前列腺肿瘤中高PTEN突变率一致，这些数据表明PTEN是该器官中的关键肿瘤抑制因子。
