Lian Zenglin, De Luca Pasquale, Di Cristofano Antonio
Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
J Cell Physiol. 2006 Aug;208(2):255-66. doi: 10.1002/jcp.20681.
Loss of PTEN is the earliest detectable genetic lesion in the endometrioid subtype of endometrial cancer (EEC), a tumor thought to be associated with an increase in unopposed estrogen activity. Pten(+/-) mice develop endometrial neoplastic lesions with full penetrance, despite having normal estrogen levels. We have utilized oligonucleotide arrays to identify the alterations in gene expression patterns associated with loss of Pten and consequent neoplastic transformation of the endometrium. We show that 487 and 330 genes are substantially up- and downregulated, respectively, in Pten(+/-) mice. Several genes whose expression levels are impacted by loss of Pten are associated with pathways and functions that are relevant to the transformation and progression processes. Strikingly, we found that the expression levels of over 100 genes known to be regulated by estrogen receptor alpha (ERalpha) are also altered in the neoplastic uterus from Pten(+/-) mice, thus mimicking a hyperestrogenic environment. These results provide in vivo evidence supporting the hypothesis that loss of Pten and subsequent Akt activation result in the activation of several ERalpha-dependent pathways that, mimicking increased estrogen signaling, may play a pivotal role in the neoplastic process.
PTEN缺失是子宫内膜样癌（EEC）中最早可检测到的基因损伤，EEC被认为是一种与无对抗雌激素活性增加有关的肿瘤。尽管雌激素水平正常，但Pten(+/-)小鼠仍会完全显性地发生子宫内膜肿瘤性病变。我们利用寡核苷酸阵列来识别与Pten缺失及随后子宫内膜肿瘤转化相关的基因表达模式变化。我们发现，在Pten(+/-)小鼠中，分别有487个和330个基因显著上调和下调。一些基因的表达水平受Pten缺失影响，它们与肿瘤转化和进展过程相关的信号通路及功能有关。引人注目的是，我们发现已知受雌激素受体α（ERα）调控的100多个基因的表达水平在Pten(+/-)小鼠的肿瘤子宫中也发生了改变，从而模拟了高雌激素环境。这些结果提供了体内证据，支持以下假说：Pten缺失及随后的Akt激活会导致几个ERα依赖信号通路的激活，这些通路模拟雌激素信号增加，可能在肿瘤发生过程中起关键作用。
