BIOLOGY OF REPRODUCTION 81, 545–552 (2009)
Published online before print 29 April 2009.
Constitutive Activation of Beta-Catenin in Uterine Stroma and Smooth Muscle Leads
to the Development of Mesenchymal Tumors in Mice1
Pradeep S. Tanwar,3Ho-Joon Lee,3LiHua Zhang,3Lawrence R. Zukerberg,4Makoto M. Taketo,5
Bo R. Rueda,3and Jose M. Teixeira2,3
Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Services,3and Department of Pathology,4
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
Department of Pharmacology,5Graduate School of Medicine, Kyoto University, Japan
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 hysterec-
tomies. Dysregulated WNT signaling through beta-catenin is a
well-established mechanism for tumorigenesis. We have devel-
oped a mouse model that expresses constitutively activated beta-
catenin in uterine mesenchyme driven by the expression of Cre
recombinase knocked into the Mu ¨llerian-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 multipa-
rous mice, suggesting that their development may be a
hormonally driven process or that changes in uterine morphol-
ogy 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 endome-
trial 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.
adenomyosis, beta-catenin, developmental biology, endometrial
stromal sarcoma, hypertrophic scarring, leiomyoma, signal
transduction, uterine fibroids, uterus, WNT signaling
Mesenchymal uterine tumors are the most common
neoplasms found in the human female reproductive tract. The
vast majority of these tumors are uterine leiomyomas (uterine
fibroids), which are benign lesions that form in the myome-
trium of an estimated 25%–50% of American women. Uterine
leiomyomas are clonal in origin and hormone responsive .
Patients may have a single uterine fibroid, but many have
multiple fibroids, and they can be located anywhere in
myometrial tissue. These tumors are commonly associated
with severe pelvic discomfort during menstruation (dysmenor-
rhea), heavy menstrual bleeding (menorrhagia), infertility,
abortion, ascites, and polycythemia. On the basis of their
location in the uterus, fibroids are subdivided into three broad
categories: subserosal, submucosal, and intramural. The size of
the fibroids can vary greatly from microscopic to tumors
weighing more than 1 kg, are often associated with significant
morbidities, and are the leading cause of hysterectomies .
Other uterine tumors such as leiomyosarcomas, endometrial
stromal sarcomas (ESSs), perivascular epitheliod cell tumors
(PEComa), and adenocarcinomas are less common but still
pose a significant burden on a women’s health and are often
fatal. The etiology of any of these mesenchymal tumors is
One of the major mechanisms of neoplastic transformation is
dysregulated b-catenin signaling. b-Catenin is the core
component of the canonical wingless-type MMTV integration
site family member (WNT) signaling pathway whose activation
leads to the translocation of b-catenin from the cytoplasm to the
nucleus and transcription of targeted genes . The role of
WNT signaling in carcinogenesis in other tissues is well
documented , but evidence for its contribution to mesenchy-
mal uterine tumor development has been limited [5–7]. WNT
signaling is indispensible for normal uterine development from
the primordial Mu ¨llerian duct [8–10], and there is accumulating
evidence to support a role for WNT signaling in postnatal
uterine functions, including implantation , decidualization
[12, 13], and perhaps remodeling after parturition.
We have been investigating b-catenin signaling in uterine
development and function using a mouse Cre recombinase
model system [14, 15] that exploits the uterine mesenchyme-
specific expression of the Mu ¨llerian inhibiting substance type
II receptor, which is also known as anti-Mu ¨llerian hormone 2
(AMHR2). We have shown that conditional deletion of
b-catenin in uterine mesenchyme leads to progressive cell fate
change from myogenesis to an adipogenic lineage . The
aim of the present study was to investigate the role of b-catenin
in uterine development further by expressing a constitutively
activated form of b-catenin in uterine mesenchyme driven by
Amhr2-Cre. When Amhr2tm3(cre)Bhr(Amhr2-Cre) mice are
crossed with Ctnnb1tm1Mmtmice , Amhr2-driven Cre
recombinase, which is expressed in ovary, oviduct, and uterus,
deletes exon3 and leads to formation of a stable form of
b-catenin in Amhr2-Cre-expressing cells and in their progeny.
1Supported by a grant from the National Institute of Child Health and
Human Development, HD052701, to J.M.T.
2Correspondence: Jose M. Teixeira, Vincent Center of Reproductive
Biology/Thier 913 Massachusetts General Hospital and Harvard
Medical School, 55 Fruit St., Boston, MA 02114. FAX: 617 726 0561;
Received: 15 December 2008.
First decision: 12 January 2009.
Accepted: 9 April 2009.
? 2009 by the Society for the Study of Reproduction, Inc.
This is an Open Access article, freely available through Biology of
Reproduction’s Authors’ Choice option.
eISSN: 1259-7268 http://www.biolreprod.org
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TANWAR ET AL.
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