Estrogen-stimulated estrogen receptor-α (ESR1) activity in the uterus largely results in enhanced proliferation and concomitant up-regulation of progesterone receptor (PGR) expression, which serves in an anti-proliferative, pro-differentiative capacity. ESR1 and PGR actions are mediated by interactions with co-regulatory proteins, which, in concert with ESR1 and PGR, activate or repress target gene transcription. In the absence of this highly regulated ESR1/PGR cross-talk, an aberrant uterine state ensues and results in reproductive dysfunctions such as infertility, endometrial cancer, endometriosis, and leiomyoma. Since ESR1/PGR co-regulatory proteins play such a critical role in determining the context-dependent outcomes of their respective actions, continued study of these proteins is warranted. The present studies investigated the consequences of the loss of Kriippel-like factor 9 (KLF9) expression, previously demonstrated to be a PGR co-activator, in endometrial cancer and endometriosis. We hypothesized that loss of KLF9 expression causes dysregulated ESR1 signaling and may be contributory to diseases such as endometriosis and endometrial cancer. We utilized in vivo (mouse) and in vitro (Ishikawa cells) models of dysregulated ESR1 signaling to determine the functional and molecular consequences of the loss of KLF9 expression. Additionally, we examined the expression of KLF9 and other genes in human endometrial cancer tissues. In our mouse endometrial cancer model, we demonstrated that the loss of Klf9 alone and in concert with perturbed ESR1 signaling enhanced the expression of several growth- and/or cancer-related genes, such as telomerase reverse transcriptase (Tert ) and FBJ murine osteosarcoma viral oncogene homolog (Fos ). The results of our mouse endometriosis studies suggest that the experimental design can be utilized to further elucidate the role of KLF9 in this disease. In our in vitro studies, we demonstrated that the loss of KLF9 expression, either in an estrogen-dependent or — independent manner, resulted in increased expression of genes such as ESR1 and TERT as well as altered expression of other Krüppel-like factor family members implicated in tumor suppression. Taken together, the results of these studies support a key regulatory role for KLF9 in ESR1 signaling. Moreover, our studies indicate that, in the context of endometrial cancer, KLF9 may function as a tumor suppressor.
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 71/10, Dissertation Abstracts International|
|Keywords:||Endometrial cancer, Estrogen recpetors, Kruppel-like factors, Uterine dysfunction, Uterine function|
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