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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #222795
Title: KRÜPPEL-LIKE FACTOR 9 AND REGULATION OF ENDOMETRIAL ESTROGEN RECEPTOR-ALPHA SIGNALING

Author
item SIMMONS, CHRISTIAN - ACNC/UAMS
item ZENG, ZHAOYANG - ACNC/UAMS
item PABONA, JOHN - ACNC/UAMS
item VELARDE, MICHAEL - UCSF
item GADDY, DANA - UAMS
item SIMMEN, FRANK - ACNC/UAMS
item SIMMEN, ROSALIA - ACNC/UAMS

Submitted to: Journal of Endocrinology
Publication Type: Abstract Only
Publication Acceptance Date: 3/15/2008
Publication Date: 6/15/2008
Citation: Simmons, C., Zeng, Z., Pabona, J.M., Velarde, M.C., Gaddy, D., Simmen, F.A., Simmen, R.C. 2008. Krüppel-like factor 9 and regulation of endometrial estrogen receptor-alpha signaling [abstract]. The Endocrine Society, 90th Annual Meeting, June 15-18, 2008, San Francisco, California. 2008 CDROM, Program No. P2-438.

Interpretive Summary:

Technical Abstract: Endometrial cancer risk is linked to aberrant estrogen receptor-alpha (ER alpha) signaling caused by increased ER alpha activation due to hyper-estrogenic environments or mutations in growth-regulatory factors. We had shown that ER alpha signaling is attenuated by the Sp1-related transcription factor Krüppel-like Factor 9 (KLF9) in the human endometrial carcinoma cell line Ishikawa through KLF9 promotion of ligand-dependent ERa down-regulation and inhibition of ligand-activated ERa transactivity. The present study examined potential links between KLF9 and the development/progression of endometrial carcinoma. qPCR arrays of human normal endometrium and endometrial tumor tissues (stages I-IV; OriGene) were assayed for KLF9 and ERa gene expression. Normal endometrium and stage I endometrial cancer (EC) tissues had higher levels (P=0.05) of KLF9 transcripts than did stages II to IV EC. ERa transcript levels were numerically higher in stages II and III than in normal endometrium and stage I, and were undetectable in stage IV EC. The functional consequence of unopposed estrogen activity in the uterus as a function of KLF9 status was evaluated in vivo. In the immature mouse model of uterine epithelial hyperplasia, KLF9 wildtype, heterozygous, and null female mice at postnatal day (PND) 25 were subcutaneously administered 17 beta-estradiol (E2) daily for 4 days, and sacrificed 24 h after the last injection. In the diethylstilbestrol (DES) mouse model that results in the development of reproductive tract tumors, female mice of the three genotypes were administered corn oil or DES (2 micro g/pup/day) on days 1-5 after birth, and sacrificed at PND28. At weaning (PND21) and at sacrifice (DES-PND28; E2-PND30), body weights (BW) were determined, and uterine and ovarian tissue weights were compared as initial measures of estrogen responsiveness. Estrogen-naive mice injected with E2 did not differ in BW with genotype. DES-treated mice at PND21 showed a significant decrease in BW relative to controls; however, this effect was independent of KLF9 status and was lost at PND28. Uterine or ovary tissue weights normalized to BW did not differ with KLF9 status in E2-treated mice. Ovary but not uterine tissues increased (P=0.058) with DES-treatment, independent of KLF9 status. Together, these findings suggest a link between KLF9 and endometrial carcinoma, and raise the possibility that KLF9 effects may be manifest at later stages of disease development. Ongoing studies will address this possibility.