Constitutive activation of Beta-catenin in uterine stroma and smooth muscle leads to the development of mesenchymal tumors in mice.
Leiomyomas and other mesenchymally derived tumors are the most common neoplasms of the female reproductive tract. Presently, very little is known about the etiology and progression of these tumors, which are the primary indication for hysterectomies. Dysregulated WNT signaling through beta-catenin is a well-established mechanism for tumorigenesis. We have developed a mouse model that expresses constitutively activated beta-catenin in uterine mesenchyme driven by the expression of Cre recombinase knocked into the Müllerian-inhibiting substance type II receptor promoter locus to investigate its effects on uterine endometrial stroma and myometrium. These mice show myometrial hyperplasia and develop mesenchymal tumors with 100% penetrance that exhibit histological and molecular characteristics of human leiomyomas and endometrial stromal sarcomas. By immunohistochemistry, we also show that both transforming growth factor beta and the mammalian target of rapamycin are induced by constitutive activation of beta-catenin. The prevalence of the tumors was greater in multiparous mice, suggesting that their development may be a hormonally driven process or that changes in uterine morphology during pregnancy and after parturition induce injury and repair mechanisms that stimulate tumorigenesis from stem/progenitor cells, which normally do not express constitutively activated beta-catenin. Additionally, adenomyosis and endometrial gland hyperplasia were occasionally observed in some mice. These results show evidence suggesting that dysregulated, stromal, and myometrial WNT/beta-catenin signaling has pleiotropic effects on uterine function and tumorigenesis.
Tanwar
Pradeep S
PS
Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Services, and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Lee
Ho-Joon
HJ
Zhang
LiHua
L
Zukerberg
Lawrence R
LR
Taketo
Makoto M
MM
Rueda
Bo R
BR
Teixeira
Jose M
JM
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D007889:Leiomyoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation / Q000502:physiology; D014591:Uterine Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014594:Uterine Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014599:Uterus / Q000378:metabolism / Q000473:pathology; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
D051176:beta Catenin