Aberrant uterine SIX1 expression may promote uterine adenocarcinoma following neonatal xenoestrogen exposure

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Authors

• AA Suen
• WN Jefferson
• E Padilla-Banks
• CE Woods
• VL Bae-Jump
• CJ Williams

Abstract

Human exposure to estrogenic chemicals during sensitive time points in development can result in reproductive diseases. Here we use a mouse model of developmental estrogen exposure to understand the mechanisms underlying uterine adenocarcinoma development. Exposing mice on days 1-5 of life to the synthetic estrogen, diethylstilbestrol (DES), or the phytoestrogen, genistein, results in high incidences of uterine adenocarcinoma by 18 months of age. However, prepubertal ovariectomy prevents this phenotype. Sine oculis-related homeobox 1 (SIX1) is a cancer-associated transcription factor that becomes permanently upregulated in the uterus after exposure. In this study we compared uterine Six1 mRNA expression, protein expression patterns, and histopathology in control and neonatal DES- or genistein-treated mice at 6, 12, and 18 months of age and tested whether prepubertal ovariectomy impacted aberrant Six1 mRNA expression. We found that Six1 mRNA expression was increased in DES and genistein-treated mice at all ages and positively correlated with uterine adenocarcinoma development. Furthermore, SIX1 protein localized to all cells in hyperplastic and neoplastic lesions in DES and genistein-treated animals. Prepubertal ovariectomy of neonatal DES-treated mice resulted in significantly lower Six1 mRNA expression than in intact or adult ovariectomized mice. These findings indicate that uterine SIX1 expression is a biomarker for exposure and disease, and suggests that SIX1 could play a role in carcinogenesis. To determine if SIX1 plays a causative role in uterine adenocarcinoma development, we are investigating if uterine specific overexpression of SIX1 induces cancer development and if uterine specific deletion of Six1 prevents cancer development following neonatal DES exposure.

Scientific Focus Area: Cancer Biology

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