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SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer.
Citation:
Suen, A., W. Jefferson, C. Wood, E. Padilla-Banks, V. Bae-Jump, AND C. Williams. SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer. Molecular Cancer Research. American Association for Cancer Research, Inc., Philadelphia, PA, 14(9):849-858, (2016).
Impact/Purpose:
Early-life exposure to estrogenic chemicals 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. The primary goal was to characterize life-stage changes in SIX1 expression using a well-established mouse model of early-life estrogen exposure.
Description:
The oncofetal protein sine oculis-related homeobox 1 (SIX1) is a developmental transcription factor associated with carcinogenesis in animal models and humans. In a model of hormonal carcinogenesis, mice neonatally exposed to the soy phytoestrogen, genistein (GEN), or the synthetic estrogen, diethylstilbestrol (DES), develop endometrial cancer as adults. We previously showed that SIX1 becomes permanently upregulated in the uteri of these mice. Here we used this mouse model to investigate the role of SIX1 expression in endometrial carcinoma development and used human tissue microarrays to explore the utility of SIX1 as a biomarker in human endometrial cancer. We found that SIX1 expression was dramatically increased at 6, 12, and 18 months of age in uteri from mice exposed neonatally to DES or GEN. SIX1 localization was associated with development of uterine carcinomas, which showed pleomorphic differentiation patterns. Basal progenitor cells and all atypical hyperplastic and neoplastic lesions showed clear nuclear labeling for SIX1, in contrast to normal endometrium. These findings indicate that developmental exposure to estrogenic chemicals can induce progressive SIX1 expression with age that is strongly associated with abnormal cell differentiation and cancer development. In human endometrial tissue samples, SIX1 was not present in normal endometrium but was expressed in a subset of endometrial cancers in patients who were more likely to have late-stage disease. These findings indicate that SIX1 expression may play a role in uterine carcinogenesis in mice and women.
