ROLE OF THE SIX1 ONCOPROTEIN IN ENDOMETRIAL CANCER CAUSED BY NEONATAL XENOESTROGEN EXPOSURE
Public Deposited- Last Modified
- March 20, 2019
- Creator
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Suen, Alisa
- Affiliation: School of Medicine, Curriculum in Toxicology
- Abstract
- Exposure to xenoestrogens during key windows of development can lead to adverse female reproductive health outcomes, including cancer. In a classical model of latent hormonal carcinogenesis, mice exposed neonatally to the synthetic estrogen diethylstilbestrol (DES) or the soy phytoestrogen genistein (GEN) develop endometrial carcinomas in late adulthood. However, the biological mechanisms driving carcinogenesis remain unclear. In this work, I investigated the role of the oncofetal protein sine oculis-related homeobox 1 homolog (SIX1) in endometrial carcinogenesis following neonatal xenoestrogen exposure and explored the utility of SIX1 as a biomarker in human endometrial cancer. I showed that neonatal exposure to GEN or DES causes aberrant endometrial SIX1 expression that persists with age and localizes to abnormally differentiated cell populations and all endometrial carcinomas. Further morphologic and molecular characterization revealed that mice exposed neonatally to GEN or DES exhibited three populations of abnormally differentiated SIX1-labeled endometrial epithelial cells that were associated with precursor lesions and carcinomas. These findings suggest that neonatal xenoestrogen exposure establishes unique SIX1-labeled cell populations that are associated with abnormal differentiation patterns in the endometrium and that may act as cancer progenitor cell populations. To explore the functional role of SIX1 in endometrial carcinogenesis, I used genetically engineered mouse models to investigate if SIX1 is necessary or sufficient for cancer development. I found that SIX1 was not necessary for development of xenoestrogen-induced endometrial carcinoma, but instead mediated abnormal differentiation of xenoestrogen-induced cell types. In addition, I showed that SIX1 overexpression alone is not sufficient to induce endometrial carcinoma development. I investigated the relevance of SIX1 as a human endometrial cancer biomarker and showed that a subset of human endometrial carcinoma biopsies express SIX1 and that expression is associated with late-stage disease. Together, I provide compelling evidence that although SIX1 alone does not act as a molecular driver of xenoestrogen-induced endometrial carcinogenesis, it is a biomarker for xenoestrogen exposure and for disease development, it is expressed in a potential cancer progenitor cell population in mice, and it contributes to abnormal endometrial epithelial differentiation.
- Date of publication
- May 2017
- Keyword
- DOI
- Resource type
- Rights statement
- In Copyright
- Advisor
- Williams, Carl
- Fry, Rebecca
- Coleman, William
- Fenton, Suzanne
- Bae-Jump, Victoria
- Degree
- Doctor of Philosophy
- Degree granting institution
- University of North Carolina at Chapel Hill Graduate School
- Graduation year
- 2017
- Language
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This work has no parents.
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