Endometrial Tumorigenesis in Pten+/- Mice Is Independent of Coexistence of Estrogen and Estrogen Receptor α
Endometrial Tumorigenesis in Pten+/- Mice Is Independent of Coexistence of Estrogen and Estrogen Receptor α
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DOI：
10.1016/j.ajpath.2012.03.006
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发表时间：
2012-06-01
影响因子：
6
通讯作者：
Ellenson, Lora H.
中科院分区：
文献类型：
--
作者：
Joshi, Ayesha;Wang, Hong;Ellenson, Lora H.
大量研究支持磷酸酶和紧张素同源(PTEN)抑癌基因突变和雌激素刺激在子宫内膜样癌发病机制中的作用。然而，PTEN信号与雌激素/雌激素受体在子宫内膜肿瘤发生中的关系仍未得到解决。我们使用基因工程小鼠作为模型来解决这种关系。带有单一缺失Pten等位基因(Pten(+/-))的小鼠会自发地发展为复杂的不典型增生，并有近20%的小鼠患上子宫内膜癌。为了确定去除内源性雌激素的效果，我们对Pten(+/-)小鼠进行了卵巢切除。尽管增生性病变的数量和严重程度有所减少，但子宫内膜的表型仍然存在，这表明Pten突变不依赖于雌激素，可以启动复杂的不典型增生的发展。为了总结雌激素水平不高的女性的情况，我们在成年雌性Pten杂合子小鼠体内植入了17粒β-雌二醇丸，导致癌症发病率增加。因为研究表明雌激素主要通过雌激素受体ERα作用于子宫内膜，所以我们产生了Pten(+/-)ERα(-/-)小鼠。引人注目的是，88.9%的Pten(+/-)ERα(-/-)小鼠发生了子宫内膜增生症/癌。此外，Pten(+/-)ERα(-/-)小鼠显示出更高的原位癌和侵袭性癌的发生率，这表明在缺乏ERA的情况下，子宫内膜肿瘤的发生可以进展。因此，Pten的改变与雌激素信号在子宫内膜癌发生发展中的关系是复杂的；本研究结果对女性子宫内膜增生症和子宫内膜癌的治疗具有重要意义。(Am J Pathol2012,180：2536-2547；http://dx.doi.org/10.1016/j.ajpath.2012.03.006)
Numerous studies support the role for mutations in the phosphatase and tensin homologue (PTEN) tumor suppressor gene and unopposed estrogen stimulation in the pathogenesis of uterine endometrioid carcinoma. However, the relation between PTEN signaling and estrogen/estrogen receptor in endometrial tumorigenesis remains unresolved. We used genetically engineered mice as a model to address this relation. Mice with a single deleted Pten allele (Pten(+/-)) spontaneously develop complex atypical hyperplasia and similar to 20% develop endometrial cancer. To determine the effect of removing endogenous estrogen, we performed oophorectomies on Pten(+/-) mice. Although there was a reduction in the number and severity of hyperplastic lesions, the endometrial phenotype persisted, suggesting that Pten mutation, independent of estrogen, can initiate the development of complex atypical hyperplasia. To recapitulate the situation in women with unopposed estrogen, we implanted 17 beta-estradiol pellets in adult female Pten heterozygous mice, resulting in increased carcinoma incidence. Because studies have shown that estrogen largely acts on the endometrium via estrogen receptor ER alpha, we generated Pten(+/-)ER alpha(-/-) mice. Strikingly, 88.9% of Pten(+/-)ER alpha(-/-) mice developed endometrial hyperplasia/carcinoma. Furthermore, Pten(+/-)ER alpha(-/-) mice showed a higher incidence of in situ and invasive carcinoma, suggesting that endometrial tumorigenesis can progress in the absence of ERa. Thus, the relation between Pten alterations and estrogen signaling in the development of endometrial carcinoma is complex; the results presented herein have important implications for the treatment of endometrial hyperplasia and carcinoma in women. (Am J Pathol 2012, 180:2536-2547; http://dx.doi.org/10.1016/j.ajpath.2012.03.006)