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Neonatal exposure of the rodent to the xenoestrogen diethylstilbestrol (DES) imparts a permanent hormonal imprint on the developing reproductive tract causing an increase in expression of estrogen-responsive genes and an increased incidence of endometrial hyperplasia [in 58% of rats] and uterine adenocarcinoma. We previously reported that endometrial complex hyperplasia with atypia in postmenopausal women is linked to overexpression of the IGF-I Receptor, loss of the negative regulator of the IGF-I pathway (PTEN), and subsequent activation of Akt (McCampbell et al., Clin Cancer Res 2006). We therefore compared the level of expression of components of the IGF-I signaling pathway (IGF-I, IGF-II, IGFBP3, IGFBP5, IGF-IR, IGF-2R, and IRS-1) as candidate genes involved in endometrial hyperplasia from rodents exposed neonatally to DES and normal vehicle treated controls in the proestrus/estrus phase. Neonatal DES exposure results in compromised ovarian function that causes a hypo-estrogenic environment, however, there is persistent expression of estrogen-responsive genes. Surprisingly, IGF-II, a gene that is not estrogen-responsive, was overexpressed in neonatal DES exposed endometrium relative to the normal proestrus/estrus phase endometrium. The expression of estrogen-responsive genes IGF-I and IGFBP3 was consistently high in the neonatal DES exposed endometrium as compared to proestrus/estrus endometrium, indicating that these genes have been reprogrammed. Additionally, the estrogen-responsive gene IRS-1, a major substrate and mediator of insulin and IGF-I receptor signaling was overexpressed in the neonatal DES exposed endometrium as compared to the proestrus/estrus endometrium. We also evaluated the expression and activation of the downstream signaling component of the IGF-I pathway, Akt. Akt expression and phosphorylation were significantly increased in neonatal DES exposed endometrium as compared to vehicle treated endometrium. Interestingly, there was a significant increase in endometrial Ki-67 positive cells in neonatal DES exposed endometrium compared to vehicle-treated controls indicating that there is increased proliferation. These results suggest that neonatal DES exposure does cause molecular reprogramming of the rodent endometrium. Interestingly, although IGF-II is overexpressed in neonatal DES exposed rodents with normal or hyperplastic endometrium, it is significantly decreased in endometrial hyperplasia as compared to the normal DES exposed endometrium. This suggests that other molecular pathways are necessary to induce endometrial hyperplasia in this model system. Our studies indicate that overexpression and activation of Akt plays a central role in both human endometrial complex hyperplasia with atypia and the rodent model of endometrial hyperplasia induced by neonatal DES exposure. #

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA