Abstract 1733: Role of the SIX1 oncofetal protein in endometrial basal cell metaplasia and carcinogenesis following neonatal exposure to diethylstilbestrol

Abstract

Abstract Early-life exposure to estrogenic chemicals can increase cancer risk, likely by disrupting normal patterns of cellular differentiation. In a model of this process, female mice exposed to the potent synthetic estrogen diethylstilbestrol (DES) on postnatal days 1-5 develop endometrial adenobasal carcinoma as adults. Neoplastic glands are comprised of abnormal populations of basal cells (cytokeratin (CK)14+), luminal cells (CK18+), and low numbers of "mixed” basal/luminal cells (CK14+/18+), all of which express the oncofetal protein sine oculis homeobox 1 (SIX1). We hypothesized that DES-induced SIX1 expression is necessary for aberrant endometrial differentiation patterns and carcinogenesis. To test this hypothesis, a conditional knockout model was generated in which floxed Six1 was excised in the uterus using progesterone receptor (Pgr) cre. The most prominent change in DES-exposed SIX1 knockout (DES-Six1d/d) mice was the absence of basal cells in the uterine horns. There was a greater than 10-fold decrease in CK14 labeling in the uterine horns of DES-Six1d/d mice compared to DES-exposed SIX1 wildtype (DES-Six1+/+) mice as determined by quantitative image analysis. However, DES-Six1d/d mice exhibited a 42% increase in cancer incidence compared to DES-Six1+/+ mice at 6 months of age (16/18 DES-Six1d/d vs. 7/15 DES-Six1+/+). Interestingly, mixed cells were still present in DES-Six1d/d mice. These findings demonstrate that SIX1 is a cellular differentiation factor necessary for DES-induced basal cells but not mixed cell development or cancer. Furthermore, these data suggest that DES-induced SIX1 expression decreases endometrial carcinogenesis by facilitating basal cell differentiation. Studies investigating the mixed cell population as a putative cancer progenitor cell population are ongoing. Interestingly, mixed cells were present in 35% (63/181) of malignant human endometrial tissue biopsies and in 0% (0/29) of normal endometrial tissue biopsies, suggesting that the DES mouse model has significant similarities to human endometrial cancer. Citation Format: Alisa A. Suen, Wendy N. Jefferson, Charles E. Wood, Anna C. Kenan, Carmen J. Williams. Role of the SIX1 oncofetal protein in endometrial basal cell metaplasia and carcinogenesis following neonatal exposure to diethylstilbestrol [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1733.