Purpose. Wnt signaling regulates the fine balance between stemness and differentiation. Here, the role of Wnt signaling to maintain the balance between estrogen-induced proliferation and progesterone-induced differentiation during the menstrual cycle, as well as during the induction of hyperplasia and carcinogenesis of the endometrium, was investigated. Experimental Design: Endometrial gene expression profiles from estradiol (E2) and E 2 + medroxyprogesterone acetate-treated postmenopausal patients were combined with profiles obtained during the menstrual cycle (PubMed; GEO DataSets). Ishikawa cells were transfected with progesterone receptors and Wnt inhibitors dickkopf homologue 1 (DKK1) and forkhead box O1 (FOXO1), measuring Wnt activation. Expression of DKK1 and FOXO1 was inhibited by use of sequence-specific short hairpins. Furthermore, patient samples (hormone-treated endometria, hyperplasia, and endometrial cancer) were stained for Wnt activation using nuclear β-catenin and CD44. Results: In vivo, targets and components of the Wnt signaling pathway (among them DKK1 and FOXO1) are regulated by E2 and progesterone. In Wnt-activated Ishikawa cells, progesterone inhibits Wnt signaling by induction of DKK1 and FOXO1. Furthermore, using siRNA-mediated knockdown of both DKK1 and FOXO1, progesterone inhibition of Wnt signaling was partly circumvented. Subsequently, immunohistochemical analysis of the Wnt target gene CD44 showed that progesterone acted as an inhibitor of Wnt signaling in hyperplasia and in well-differentiated endometrial cancer. Conclusion: Progesterone induction of DKK1 and FOXO1 results in inhibition of Wnt signaling in the human endometrium. This Wnt inhibitory effect of progesterone is likely to play a rate-limiting role in the maintenance of endometrial homeostasis and, on its loss, in tumor onset and progression toward malignancy.

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Keywords Hermes antigen, Wnt protein, article, beta catenin, cancer inhibition, carcinoma cell, cell proliferation, clinical article, controlled study, dickkopf 1 protein, endometrium, endometrium cancer, endometrium hyperplasia, estradiol, female, gene activation, gene expression profiling, gene expression regulation, gene induction, gene repression, gene silencing, gene targeting, genetic transfection, hormonal carcinogenesis, hormonal regulation, hormone substitution, human, human cell, human tissue, immunohistochemistry, medroxyprogesterone acetate, menstrual cycle, postmenopause, priority journal, progesterone receptor, protein determination, protein function, short hairpin RNA, signal transduction, tissue differentiation, transcription factor FKHR
Persistent URL dx.doi.org/10.1158/1078-0432.CCR-09-0814, hdl.handle.net/1765/17497
Citation
Wang, Y, Hanifi-Moghaddam, P, Hanekamp, E.E, Kloosterboer, H.J, Franken, P.F, Veldscholte, J, … Blok, L.J. (2009). Progesterone inhibition of Wnt/β-catenin signaling in normal endometrium and endometrial cancer. Clinical Cancer Research, 15(18), 5784–5793. doi:10.1158/1078-0432.CCR-09-0814