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Title: Response of adult mouse uterus to early disruption of estrogen receptor-alpha signaling is influenced by Krüppel-like factor 9

item Simmons, Christian - Arkansas Children'S Nutrition Research Center (ACNC)
item Pabona, John Mark - Arkansas Children'S Nutrition Research Center (ACNC)
item Zeng, Zhaoyang - Arkansas Children'S Nutrition Research Center (ACNC)
item Velarde, Michael - Buck Institute For Age Research
item Gaddy, Dana - University Arkansas For Medical Sciences (UAMS)
item Simmen, Frank - Arkansas Children'S Nutrition Research Center (ACNC)
item Simmen, Rosalia - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: Journal of Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/17/2010
Publication Date: 5/3/2010
Citation: Simmons, C., Pabona, J., Zeng, Z., Velarde, M., Gaddy, D., Simmen, F., Simmen, R. 2010. Response of adult mouse uterus to early disruption of estrogen receptor-alpha signaling is influenced by Krüppel-like factor 9. Journal of Endocrinology. 205(2):147-157.

Interpretive Summary: Our research has determined that newborn mice with a mutation in a gene called Krüppel-like factor 9 (KLF9), when compared to normal mice, have an abnormal response to early estrogenic exposure. Excessive estrogen stimulation has been associated with many diseases including uterine endometrial cancer. We believe that the abnormal response of the KLF9 mutant mice could make them more likely to develop uterine cancer later in life. In many cases, we found that uterine structure and uterine gene expression were changed by KLF9 mutation both with and without early estrogen exposure. Interestingly, by examining a published study about human uterine endometrial cancer, we found changes in the levels of KLF9 and other genes that were similar to those found our mouse studies. Thus, our findings suggest that KLF9 is a novel gene of interest in the development of uterine endometrial cancer. Ongoing studies in our lab will determine if the KLF9 mutant mice develop uterine endometrial cancer faster than normal mice.

Technical Abstract: Inappropriate early exposure of the hormone-responsive uterus to estrogenic compounds is associated with increased risk for adult reproductive diseases including endometrial cancers. While the dysregulation of estrogen receptor-alpha (ESR1) signaling is a well-acknowledged early event in tumor initiation, mechanisms contributing to the promotion and/or maintenance of enhanced ESR1 activity later in life and subsequent up-regulation of oncogenic pathways remain poorly understood. We previously showed that the transcription factor Kruppel-like Factor 9 (KLF9) represses ESR1 expression and activity in Ishikawa endometrial glandular epithelial cells. We hypothesized that KLF9 functions as a tumor suppressor and loss of its expression enhances ESR1 signaling. Here, we evaluated the contribution of KLF9 to early perturbations in uterine ESR1 signaling pathways elicited by synthetic estrogen diethylstilbestrol (DES) administration to wild-type (WT) and Klf9 null (KO) mice on postnatal days 1-5. Uterine tissues collected at PND84 were subjected to histological, immunological, and molecular analyses. Compared to WT, KO mice demonstrated larger endometrial glands and lower endometrial gland numbers; early DES exposure exacerbated these differences. KLF9 loss of expression resulted in increased glandular ESR1 immunoreactivity with DES, without change in serum estradiol levels. QPCR analyses indicated altered expression of genes commonly dysregulated in endometrial cancers (Akt1,Mmp9, Slpi, Tgf-beta1) and those involved in growth regulation (Fos, Myc, Tert, Syk), with loss of Klf9, alone or in concert with DES. Our data further link KLF9 to the control of endometrial ESR1 signaling and suggest that silencing of this transcription factor may contribute to endometrial dysfunction initiated by aberrant estrogen action.