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SIX1 oncoprotein is necessary for abnormal uterine basal cell development in mice exposed neonatally to DES.
Suen, A., W. Jefferson, C. Williams, AND C. Wood. SIX1 oncoprotein is necessary for abnormal uterine basal cell development in mice exposed neonatally to DES. NIEHS Science Day, RTP, NC, November 02 - 04, 2017.
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.
Exposing female mice on neonatal days 1-5 to the synthetic estrogen diethylstilbestrol (DES) 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. In the current study, we investigate whether 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 floxed Six1 is excised in the uterus using the PgR-cre transgene. At 6 months of age, uterine carcinoma was observed in 4/10 (40%) of DES-exposed wildtype (Six1+/+) mice and 7/9 (78%) of DES-exposed Six1 conditional knockout (Six1d/d) mice but not in either of the control groups. The presence of atypical hyperplasia and carcinomas in the absence of SIX1 indicates that SIX1 is not required for DES-induced carcinogenesis in the uterus. However, we found that basal cell and squamous metaplasia was significantly reduced in DES-exposed Six1d/d mice, with >10-fold fewer K14-positive basal cells in endometrial glands of Six1d/d mice suggesting SIX1 is necessary for abnormal basal cell differentiation. Taken together, 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 DES-induced basal-type progenitor cells. This abstract does not reflect U.S. EPA policy.
Record Details:Record Type: DOCUMENT (PRESENTATION/POSTER)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
INTEGRATED SYSTEMS TOXICOLOGY DIVISION