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The SIX1 Oncoprotein Mediates Aberrant Endometrial Basal Cell Development Following Neonatal Exposure to Diethylstilbestrol
Citation:
Suen, A., W. Jefferson, C. Williams, AND C. Wood. The SIX1 Oncoprotein Mediates Aberrant Endometrial Basal Cell Development Following Neonatal Exposure to Diethylstilbestrol. Society of Toxicologic Pathology, Indianapolis, IN, June 17 - 21, 2018.
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:
Early-life exposures can disrupt cellular differentiation and contribute to increased cancer risk later in life. In a model of developmental estrogen exposure, female mice exposed on postnatal day (PND) 1-5 to diethylstilbestrol (DES) develop a high incidence of endometrial adenocarcinoma. Carcinogenesis is associated with the establishment of abnormal basal cells and low numbers of "mixed” cells that co-express the basal and luminal cell markers cytokeratin (CK) 14 and 18. These putative cancer progenitor cell types and all neoplastic lesions aberrantly express the oncofetal protein sine oculis homeobox 1 (SIX1). We hypothesize that SIX1 is necessary for DES-induced differentiation of these abnormal cell types and carcinogenesis. To test this hypothesis, a conditional knockout mouse model was generated in which floxed Six1 was excised in the uterus using the PgR-cre transgene. Ablation of uterine SIX1 was confirmed by qPCR and immunoblotting. The most prominent change in DES-exposed SIX1 knockout (DES-Six1d/d) mice was the absence of basal cells in the uterine horns. Quantitative image analysis indicated a >10-fold decrease in CK14 labeling in the uterine horns of DES-Six1d/d mice compared to DES-exposed SIX1 wildtype (DES-Six1+/+) mice. However, DES-Six1d/d mice exhibited a ~40% increase in cancer incidence as compared to DES-Six1+/+ mice (7/9 DES-Six1d/d; 4/10 DES-Six1+/+) at 6 months of age. Interestingly, mixed cells co-expressing CK14/18 were still present in DES-Six1d/d mice. Together, these data demonstrate that SIX1 is a cellular differentiation factor necessary for DES-induced basal cell development but is not required for establishment of mixed cells or cancer. Furthermore, these data suggest that mixed cells may act as the cancer progenitor cell population and that SIX1 may mediate cancer progression by decreasing the population of mixed cells through basaloid differentiation. This abstract does not reflect U.S. EPA policy.