Influence of endocrine disturbance in endometrial carcinogenesis in recombinant PTEN mice.

人类子宫内膜癌，以及复杂非典型增生（CAH），是雌激素相关的，经常有PTEN基因突变。然而，雌激素和PTEN突变在体内子宫内膜癌发生中的相互作用尚不清楚。为了解决这个问题，我们研究了新生儿雌激素治疗是否会增加mPTEN杂合（+/-）突变小鼠（子宫内膜癌的动物模型）中CAH和癌的发生率。从出生后第1 ~ 5天，每天皮下注射低剂量的己烯雌酚（1 ng/g/d）、植物雌激素中的染料木素（50 μg/g/d）、雌三醇（E_3） （4 μg/g/d）和对照物（乙醇和玉米油）。52周龄时，观察子宫内膜形态学变化及Hoxa 10和Hoxa 11的表达。这些Hoxa基因是腹部B型同源盒基因，通常调节苗勒管的分化。新生儿雌激素治疗可显著降低mPTEN+/-小鼠CAH和子宫内膜腺癌的发生率。巧合的是，所有治疗均显著降低了间质细胞密度，CAH和腺癌很少在受影响的子宫内膜间质附近的上皮中发生。此外，新生染料木素和E_3处理小鼠子宫中Hoxa 10的表达，以及所有处理小鼠子宫中Hoxa 11的表达均显著低于单独处理小鼠。综上所述，新生儿雌激素暴露诱导间质萎缩和/或透明化，同时抑制Hoxa 10和Hoxa 11的表达，并对pten相关的肿瘤发生产生抑制作用。这些发现为子宫内膜癌发生过程中子宫内膜上皮和间质之间的相互作用提供了新的认识。

Human endometrial carcinomas, as well as complex atypical hyperplasias (CAH), are estrogen-related and frequently have mutations in the PTEN gene. However, the mutual contribution of estrogen and PTEN mutations to endometrial carcinogenesis in vivo is unknown. To address this issue, we investigated whether neonatal estrogenic treatments augment the incidence of CAH and carcinomas in mPTEN heterozygous (+/-) mutant mice, an animal model for endometrial carcinoma. Low doses of diethylstilbestrol (1 ng/g/day), genistein (50 μg/g/day) in phytoestrogens, estriol (E_3) (4 μg/g/day) and vehicle (ethanol and corn oil) were administered subcutaneously daily to neonatal pups from the 1st to 5th day after birth. At 52 weeks of age, the morphological changes in endometrium, and uterine expression of Hoxa 10 and Hoxa 11, were evaluated. These Hoxa genes are abdominal B type homeobox genes, which normally regulate differentiation of the mullerian duct. The incidence of CAH and adenocarcinomas of the endometrium was significantly decreased by the neonatal estrogenic treatments in the mPTEN+/- mice. Coincidentally, all treatments significantly decreased the stromal cell density, and CAH and adenocarcinomas rarely developed in the epithelium adjacent to the affected endometrial stroma. Moreover, the uterine expression of Hoxa 10 in mice with neonatal genistein and E_3 treatments, and that of Hoxa 11 in mice with all treatments, was significantly lower when compared with vehicle alone. Taken together, neonatal estrogenic exposure induced stromal atrophy and/or hyalinization accompanied by repressed expression of Hoxa 10 and Hoxa 11, and exerted an inhibitory effect on PTEN-related tumorigenesis. These findings provide new insight into the interaction between endometrial epithelium and stroma in endometrial carcinogenesis in vivo.