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Title: Transcription factor krüppel-like factor 9 (klf9) as potential predictor of dysfunctional estrogen receptor-a signaling in the uterus

Author
item SIMMONS, CHRISTIAN - Arkansas Children'S Nutrition Research Center (ACNC)
item PABONA, JOHN MARK - Arkansas Children'S Nutrition Research Center (ACNC)
item BURNETT, ALEXANDER - University Arkansas For Medical Sciences (UAMS)
item FRIEDMAN, THEODORE - University Arkansas For Medical Sciences (UAMS)
item SPATARO, MICHAEL - University Arkansas For Medical Sciences (UAMS)
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: Endocrine Society Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 3/15/2010
Publication Date: 6/28/2010
Citation: Simmons, C., Pabona, J., Burnett, A., Friedman, T., Spataro, M., Gaddy, D., Simmen, F., Simmen, R. 2010. Transcription factor krüppel-like factor 9 (klf9) as potential predictor of dysfunctional estrogen receptor-a signaling in the uterus [abstract]. Endocrine Reviews. 31(3)Supplement 1:S1720.

Interpretive Summary:

Technical Abstract: Kruppel-like factors (KLFs) are zinc finger-containing transcription factors that are implicated in diverse physiological processes in the reproductive tract. We previously showed that KLF9, a 33kDa protein family member, influenced estrogen receptor-alpha (ER alpha) expression and activity in mouse and human uterine cells, suggesting its potential role as a nuclear receptor co-regulator. KLF9 knockdown in Ishikawa endometrial cancer cells with siRNAs impaired ER alpha autoregulation, leading to enhanced ER alpha signaling. Further, we and others have reported the loss of KLF9 expression in human endometrial tumors. To determine the contribution of KLF9 to ER alpha signaling in vivo, we superimposed Klf9 null mutation with the diethylstilbestrol (DES) model of carcinogenesis in mice and evaluated uterine morphological and molecular indices as predictors of dysfunctional estrogenic stimulation. Wildtype (WT) and Klf9 null (KO) female mice were injected with sesame oil or DES (2 micro g/pup/day) on postnatal (PND) days 1-5, and uteri were collected at PND84. Compared to WT, KO mice had larger and reduced numbers of endometrial glands; DES exposure exacerbated these differences. KLF9 loss resulted in increased glandular ER alpha immunoreactivity with DES, without affecting serum estradiol levels. QPCR analyses of WT and KO uterine RNAs indicated altered expression of genes commonly dysregulated in endometrial cancers (Akt1, Mmp9, Slpi, Tgf beta 1) and those involved in growth regulation (Fos, Myc, Tert, Syk), alone and in concert with DES. Since early DES exposure leading to aberrant adult uterine phenotypes has been linked to epigenetic mechanisms involving changes in chromatin modification enzyme expression, uterine transcript levels of DNA methyltransferase-1(Dnmt1) and histone deacetylase (Hdac) 3, 6, and 9 were also evaluated. Hdac9 transcript levels were increased with loss of Klf9 and early DES exposure. Collectively, these data support a functional KLF9/ER alpha molecular network in the uterus and suggest that KLF9 and its downstream targets may constitute 'molecular fingerprints' for early diagnosis of endometrial carcinoma arising from dysregulated ER alpha signaling. The predictive significance of these altered genes in clinically relevant tissues will be addressed by analyses of endometrial tumors and adjacent non-tumor tissues collected from women undergoing surgery.