Citation:

Suen, A., W. Jefferson, C. Wood, AND C. Williams. SIX1 regulates aberrant endometrial epithelial cell differentiation and cancer trajectory. Molecular Cancer Research. American Association for Cancer Research, Inc., Philadelphia, PA, 17(12):2369-2382, (2019). https://doi.org/10.1158/1541-7786.MCR-19-0475

Impact/Purpose:

Cancer is now recognized as a life-stage disease. While most human cancers are associated with increased age, the genetic and epigenetic processes that drive and ultimately characterize malignancy often begin much earlier in life. Environmental factors may accelerate these processes and thereby alter risk years after an original exposure or event. For chemical carcinogens, we now know from both experimental and epidemiologic studies that epigenetic changes initiated early in life can increase future susceptibility to cancer, often beyond that seen with adult-only exposure, and that the scope of these latent effects extends well beyond direct mutagenic agents. This evidence has highlighted the need for biomarkers that are persistently altered following exposure to a potential carcinogen and clearly associated with risk later in life. Prior evidence from animal and epidemiologic studies has shown that exposure to exogenous estrogens during key windows of development can lead to adverse reproductive health outcomes later in life, including cancer and infertility. In one of the most widely used models of this pathway, neonatal treatment of female CD-1 outbred mice with estrogens such as DES and GEN induces a high incidence of uterine carcinoma by 18 months of age (Suen et al. 2016). However, the carcinogenic process and associated pathways are not well understood. This case study evaluates pathways and early susceptibility biomarkers of this effect.

Description:

Disruption of normal cellular differentiation pathways early in life can increase cancer risk. In an established model of this process, female mice exposed neonatally to the synthetic estrogen diethylstilbestrol (DES) develop metaplastic and neoplastic uterine endometrial changes as adults. The abnormal endometrial glands aberrantly express the oncofetal protein sine oculis homeobox 1 (SIX1) and are comprised of basal cells, luminal cells, and low numbers of poorly differentiated cells with mixed basal and luminal characteristics [cytokeratin (CK)14+/18+]. Here we tested whether SIX1 expression was necessary for DES-induced aberrant endometrial differentiation and carcinogenesis using conditional knockout mice lacking Six1 in the uterus (Six1d/d). Vehicle-treated control (CON) Six1d/d mice developed focal uterine glandular dysplasia and carcinoma in situ, indicating that SIX1 is required for normal uterine glandular differentiation. Six months following neonatal DES exposure, Six1d/d mice exhibited a 42% higher incidence of endometrial cancer relative to Six1+/+ mice and had >10-fold fewer CK14+ basal cells in the uterine horns. Interestingly, the percentage of mice with neoplastic lesions containing CK14+/18+ cells was similar regardless of genotype. These findings suggest that SIX1 delays DES-induced endometrial carcinogenesis by promoting basal differentiation of a pool of cancer cells of origin. In human endometrial tissue biopsies, CK14+/18+ cells were present in 35% of cases classed as malignant and positively correlated with increased stage and grade but were not present in normal endometrial tissue. Thus, there are significant similarities between the DES-induced endometrial cancer mouse model and human endometrial cancer. The association of poorly differentiated CK14+/18+ cells with human endometrial cancer provides a novel cancer biomarker and could lead to new therapeutic strategies.

URLs/Downloads:

Record Details: