Citation:

Suen, A., W. Jefferson, C. Wood, E. Padilla-Banks, AND C. Williams. The SIX1 oncoprotein mediates uterine carcinogenesis following neonatal xenoestrogen exposure. 2017 Annual Meeting of the Society of Toxicology, Baltimore, MD, March 12 - 16, 2017.

Impact/Purpose:

Early-life exposure to estrogenic chemicals in the environment has been associated with increased susceptibility to cancer and other adverse reproductive health outcomes later in life. Biological pathways driving these effects are still largely unknown. This case study investigated the role of a developmental protein called SIX1 as a molecular driver and biomarker of latent estrogenic effects in a mouse model of early-life estrogen exposure. The ultimate goal of this work is to enable more rapid identification of AOPs for cancer incorporating life stage susceptibility.

Description:

Xenoestrogen exposure during key windows of development can lead to adverse reproductive health outcomes later in life, including cancer. In a classical model of hormonal carcinogenesis, exposing mice on neonatal days 1-5 to the synthetic estrogen, diethylstilbestrol (DES; 1 mg/kg/day), results in high incidence of uterine carcinoma by 18 months of age. Sine oculis-related homeobox 1 (SIX1) is a cancer-associated transcription factor that dramatically increases in the uteri of mice exposed neonatally to DES, persists with age, and localizes to abnormal uterine basal cells and all neoplastic lesions, suggesting a functional role in uterine carcinogenesis. Here we investigate if uterine SIX1 expression is necessary or sufficient for DES-induced uterine carcinogenesis. First, we are using a conditional knockout mouse model in which Six1 is deleted in the uterus using the progesterone receptor (PR)-cre transgene. In homozygous floxed-Six1 mice expressing PR-cre, we confirmed efficient deletion by showing that neonatal DES-exposure does not induce uterine expression of Six1 transcripts. Preliminary analyses indicate that conditional uterine Six1 deletion decreased the number of aberrant P63- and cytokeratin 14-positive basal cells in the endometrial glands of DES-exposed mice at 6 months of age, suggesting that SIX1 contributes to the development of early progenitor cells. Second, we are investigating if SIX1 overexpression is sufficient to induce carcinogenesis in the absence of neonatal DES exposure. A transgenic mouse line was generated in which SIX1 should be expressed in tissues expressing the PR-cre transgene. We confirmed uterine SIX1 overexpression in this mouse line by western blotting and immunohistochemistry. We are now aging these transgenic mice to determine if aberrant SIX1 expression in the uterus alone is sufficient to induce uterine carcinogenesis. Collectively, these targeted models will inform the role of SIX1 as a molecular driver and biomarker for the development of xenoestrogen-induced uterine cancer. This abstract does not reflect U.S. EPA policy.

Record Details: