Neonatal estrogenic exposure suppresses PTEN-related endometrial carcinogenesis in recombinant mice

Abstract

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 murine PTEN (mPTEN) heterozygous ( þ /À) mutant mice, an animal model for endometrial carcinoma. Low doses of diethylstilbestrol (1 ng/g/day), genistein (50 lg/g/day) in phytoestrogens, estriol (E 3 ) (4 lg/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 the 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 Mü llerian duct. The incidence of CAH and adenocarcinomas of the endometrium was significantly decreased by the neonatal estrogenic treatments in the mPTEN þ /À 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.

Multi-targeted therapy of cancer by genistein

“…Additionally genistein is also reported to substantially inhibit skin carcinogenesis and cutaneous aging induced by ultraviolet (UV) light in mice [99]. In a murine PTEN (mPTEN) heterozygous (+/−) mutant mouse model for endometrial carcinoma, as well as in estrogenrelated endometrial carcinogenesis, genistein exerted an inhibitory effect on PTEN-related tumorigenesis [101]. Genistein also attenuated gastric carcinogenesis promoted by sodium chloride in a rat model of gastric cancer [102].…”

Glucose Transporters in Sex Steroid Hormone Related Cancer

“…Reduction of endometrial ER levels and activity dramatically reduces the neoplastic effect of PTEN loss in the endometrium [182]. Furthermore, neonatal estrogenic exposure exerts an inhibitory effect on PTENrelated endometrial tumorigenesis [183]. Estrogen may down-regulate PTEN activity by increasing its phosphorylation, but progesterone is likely to regulate the PTEN pool by decreasing its phosphorylation and increasing its protein level [183].…”

“…Furthermore, neonatal estrogenic exposure exerts an inhibitory effect on PTENrelated endometrial tumorigenesis [183]. Estrogen may down-regulate PTEN activity by increasing its phosphorylation, but progesterone is likely to regulate the PTEN pool by decreasing its phosphorylation and increasing its protein level [183]. There is mounting evidence indicating that hormones regulate HIF-1 in hormone-dependent cancers [46].…”

Mutual Contribution of Pten and Estrogen to Endometrial Carcinogenesis in a PtenloxP/loxP Mouse Model

“…Complex atypical hyperplasia was demonstrated in 7 of 8 Pten heterozygous mice (87.5%), with 37.5% progressing to well-differentiated endometrial carcinoma. 16 Pten inactivation may be caused by a variety of mechanisms. Mutations or deletions resulting in loss of heterozygosity at chromosome 10q23 are detectable in 37% to 61% of cancers.…”