Citation:

Suen, A., W. Jefferson, C. Wood, E. Padilla-Banks, AND C. Williams. The role of SIX1 oncoprotein in uterine carcinogenesis caused by 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, infertility, 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:

In a classical model of latent 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. However, the biological mechanisms driving DES-induced carcinogenesis remain unclear. We previously showed that the sine oculis homeobox homolog 1 (SIX1) oncoprotein was aberrantly expressed in the uteri of mice exposed neonatally to DES, persisted with age, and localized to abnormal uterine basal cells within all neoplastic lesions. Here, we investigated if SIX1 is necessary for uterine basal cell differentiation and carcinogenesis in mice exposed neonatally to DES. We used a conditional knockout mouse model in which Six1 is deleted in the uterus using the progesterone receptor-cre transgene. We confirmed that Six1 is effectively deleted in this model and not induced by neonatal DES exposure. At 6 months of age, uterine carcinoma was observed in 40% of DES-exposed wildtype mice (4/10) and 78% of DES-exposed Six1 conditional knockout mice (7/9) but not in controls. All cancers showed basal cell differentiation, as indicated by cytokeratin (CK) 14 expression. However, DES exposure resulted in >10-fold higher CK14-positive basal cells in endometrial glands of wildtype mice compared to SIX1 conditional knockout mice. Absence of SIX1 did not alter DES effects on luminal cell numbers, as indicated by CK18 expression. These data indicate that SIX1 expression is not required for DES-induced carcinogenesis in the uterus but rather serves as a key differentiation factor for aberrant basal-type progenitor cells. This abstract does not reflect U.S. EPA policy.

Record Details: