SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer.
The oncofetal protein sine oculis-related homeobox 1 (SIX1) is a developmental transcription factor associated with carcinogenesis in several human cancer types but has not been investigated in human endometrial cancer. 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. Previously, we demonstrated that SIX1 becomes aberrantly expressed 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. In mice neonatally exposed to GEN or DES, the Six1 transcript level increased dramatically over time in uteri at 6, 12, and 18 months of age and was associated with development of endometrial carcinoma. SIX1 protein localized within abnormal basal cells and all atypical hyperplastic and neoplastic lesions. These findings indicate that developmental estrogenic chemical exposure induces persistent endometrial SIX1 expression that is strongly associated with abnormal cell differentiation and cancer development. In human endometrial tissue specimens, SIX1 was not present in normal endometrium but was expressed in a subset of endometrial cancers in patients who were also more likely to have late-stage disease. These findings identify SIX1 as a disease biomarker in a model of hormonal carcinogenesis and suggest that SIX1 plays a role in endometrial cancer development in both mice and women.



The SIX1 oncoprotein is aberrantly expressed in the endometrium following developmental exposure to estrogenic chemicals, correlates with uterine cancer, and is a biomarker in human endometrial cancers. Mol Cancer Res; 14(9); 849-58. ©2016 AACR.
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina. Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Alisa A
AA
Suen
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina.
Wendy N
WN
Jefferson
Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina.
Charles E
CE
Wood
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina.
Elizabeth
E
Padilla-Banks
Division of Gynecologic Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Victoria L
VL
Bae-Jump
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina. Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. williamsc5@niehs.nih.gov Victoria.Bae-Jump@unchealth.unc.edu.
Carmen J
CJ
Williams
D000818:Animals; D000831:Animals, Newborn; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D004054:Diethylstilbestrol; D004195:Disease Models, Animal; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D019833:Genistein; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D014157:Transcription Factors / Q000378:metabolism; D014599:Uterus / Q000378:metabolism / Q000473:pathology
D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; C099236:SIX1 protein, human; D014157:Transcription Factors; D004054:Diethylstilbestrol; D019833:Genistein