Progesterone inhibition of Wnt/beta-catenin signaling in normal endometrium and endometrial cancer.
OBJECTIVE
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.


METHODS
Endometrial gene expression profiles from estradiol (E(2)) 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 beta-catenin and CD44.


RESULTS
In vivo, targets and components of the Wnt signaling pathway (among them DKK1 and FOXO1) are regulated by E(2) 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.


CONCLUSIONS
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.
Wang
Yongyi
Y
Department of Obstetrics and Gynecology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.
Hanifi-Moghaddam
Payman
P
Hanekamp
Eline E
EE
Kloosterboer
Helenius J
HJ
Franken
Patrick
P
Veldscholte
Jos
J
van Doorn
Helena C
HC
Ewing
Patricia C
PC
Kim
J Julie
JJ
Grootegoed
J Anton
JA
Burger
Curt W
CW
Fodde
Riccardo
R
Blok
Leen J
LJ
D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C501126:DKK1 protein, human; D004967:Estrogens; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D011374:Progesterone