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review article
mechanisms of disease
Dan L. Longo, M.D., Editor

Uterine Fibroids
From the Department of Obstetrics and
Gynecology, Feinberg School of Medicine, Northwestern University, Chicago.
Address reprint requests to Dr. Bulun at
Prentice Womens Hospital, 250 E. Superior St., Ste. 03-2306, Chicago, IL 60611,
or at s-bulun@northwestern.edu.
N Engl J Med 2013;369:1344-55.
DOI: 10.1056/NEJMra1209993
Copyright 2013 Massachusetts Medical Society

1344

Serdar E. Bulun, M.D.

terine fibroids (leiomyomas) represent the most common tumor

in women. These lesions disrupt the functions of the uterus and cause excessive uterine bleeding, anemia, defective implantation of an embryo, recurrent pregnancy loss, preterm labor, obstruction of labor, pelvic discomfort, and urinary incontinence and may mimic or mask malignant tumors. By the time they reach
50 years of age, nearly 70% of white women and more than 80% of black women
will have had at least one fibroid; severe symptoms develop in 15 to 30% of these
women.1,2 Uterine fibroids in black women are significantly larger at diagnosis
than those in white women, are diagnosed at an earlier age, and are characterized
by more severe symptoms and a longer period of sustained growth.3-5 Approximately
200,000 hysterectomies, 30,000 myomectomies, and thousands of selective uterineartery embolizations and high-intensity focused ultrasound procedures are performed
annually in the United States to remove or destroy uterine fibroids. The annual economic burden of these tumors is estimated to be between $5.9 billion and $34.4 billion.6
There may be one predominant uterine fibroid or a cluster of many fibroids
(Fig. 1). Very large fibroids can cause the uterus to expand to the size reached at
6 or 7 months of pregnancy. The location and size of the fibroid in the uterus are
critical determinants of its clinical manifestations. As compared with other fibroids, submucous fibroids that extend into the uterine cavity are the most disruptive to endometrial integrity, implantation, and the capacity of the myometrium to
contract and stop menstrual bleeding from the endometrial blood vessels; thus,
even small submucous fibroids are associated with excessive or irregular bleeding,
infertility, and recurrent pregnancy loss. In contrast, subserous fibroids that grow
out into the peritoneal cavity can exert pressure that is sensed by the patient as
pelvic discomfort only if they reach a certain size. Intramural fibroids that reside
in the myometrial wall represent an intermediary group. Regardless of their size
or location, fibroids may have paracrine molecular effects on the adjacent endometrium that are extensive enough to cause excessive uterine bleeding or defective
implantation.7
Uterine fibroids are monoclonal tumors that arise from the uterine smoothmuscle tissue (i.e., the myometrium).8 Histologically, fibroids are benign neoplasms composed of disordered smooth-muscle cells buried in abundant quantities of extracellular matrix (Fig. 1). The cells proliferate in vivo at a modest rate.
Formation of the extracellular matrix also accounts for a substantial portion of
tumor expansion. Uterine fibroids are almost always benign.9
A striking feature of uterine fibroids is their dependency on the ovarian steroids
estrogen and progesterone.10 Ovarian activity is essential for fibroid growth, and
most fibroids shrink after menopause. The sharp elevations and declines in the
production of estrogen and progesterone that are associated with very early pregnancy and the postpartum period have a dramatic effect on fibroid growth.11-13
Gonadotropin-releasing-hormone (GnRH) analogues, which suppress ovarian activity and reduce circulating levels of estrogen and progesterone, shrink fibroids
and reduce associated uterine bleeding.14
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mechanisms of disease

B Fibroids removed from the same uterus

A Single fibroid
Normal
myometrium
Fibroid
Obliterated
endometrial
cavity
Cervical
canal

C Normal myometrial tissue

D Fibroid tissue

ECM

50.0 m

50.0 m

Figure 1. Gross Anatomical and Histologic Features of Fibroids.

A single large fibroid may occupy the entire uterine fundus (Panel A, bivalved) and obliterate the endometrial cavity,
but many fibroids of varying size can also grow in a single uterus (Panel B). Normal myometrium contains well-
organized bundles of smooth-muscle cells with relatively small nuclei and abundant cytoplasm (Panel C, hematoxylin and eosin). With the growth of fibroid tissues, islands of disordered smooth-muscle cells separated by abundant
extracellular matrix (ECM) (Panel D; hematoxylin and eosin) are prominent in fibroid tissue. Fibroid smooth-muscle
cells contain fairly large and conspicuous nuclei. Photographs in Panels B, C, and D are courtesy of Dr. Jian-Jun Wei,
Northwestern University, Chicago.

A limited number of genetic defects transmitted by germ cells have been associated with familial uterine fibroid syndromes.15 Most notable
are germline mutations causing fumarate hydratase deficiency, which predisposes women to the
development of multiple uterine fibroids.16 In
addition, a variety of somatic chromosomal rearrangements have been described in up to 40% of
uterine fibroids.17 Recently, whole-genome sequencing showed that chromosomal rearrangements are often complex, best described as single events consisting of multiple chromosomal
breaks and random reassembly.18 In an earlier
study, a somatic single-gene defect was found in
a majority of uterine fibroid tumors; this group
of mutations affects the gene encoding mediator
complex subunit 12 (MED12).19
There are also genomewide differences in DNA
methylation between fibroid tissue and the adjacent normal myometrium.20 A large number of

other molecular defects involving transcriptional and posttranscriptional events, microRNAs

(miRNAs), and signaling pathways have also
been described.21-28 Although some of the effects of uterine fibroids on cell proliferation,
apoptosis, and extracellular matrix formation
have been identified, little is known about their
effects on other cellular processes in fibroid
growth, such as autophagy and senescence. This
review focuses on some recent developments in
fibroid research, including the role of stem cells,
somatic genetic and epigenetic defects, and the
action of estrogen and progesterone and their
cross-talk with various signaling pathways.

CEL LUL A R OR IGINS

The cellular origin of uterine fibroids remains
unknown. Several observations support the notion that each fibroid originates from the trans-

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1345

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formation of a single somatic stem cell of the

myometrium under the influence of ovarian hormones. Early genetic studies suggest that fibroids
are monoclonal tumors.8 Human and mouse
myometrial tissues contain multipotent somatic
stem cells. By means of asymmetric division, this
subset of tissue cells undergoes self-renewal and
produces daughter cells under the influence of
reproductive hormones (possibly ovarian hormones); this process is responsible for regeneration.29-31 Human uterine fibroid tissue contains
fewer stem cells than normal myometrium.32,33
However, stem cells derived from fibroid tissue
not the myometrium carry MED12 mutations, which suggests that at least one genetic hit
initially transforms a myometrial stem cell, which
subsequently interacts with the surrounding
myometrial tissue to give rise to a fibroid tumor
(Fig. 2).33
In vivo experimental models reveal that the
growth of human fibroid tumors that are dependent on estrogen and progesterone requires the
presence of multipotent somatic stem cells.33,34
As compared with the main fibroid-cell population or with normal myometrial cells, fibroid
stem cells express remarkably low levels of receptors for estrogen and progesterone. The
growth of fibroid stem cells requires the presence of myometrial cells with higher levels of
the estrogen and progesterone receptors and
their ligands, suggesting that the action of steroid hormones on fibroid stem cells is mediated
by myometrial cells in a paracrine fashion.33,34 It
is likely that this paracrine interaction with the
surrounding cells supports the self-renewal of fibroid stem cells (Fig. 2). Both myometrial and
fibroid multipotent somatic stem cells lack markers for smooth-muscle cells, and in addition to
their differentiation into smooth-muscle cells in
vivo, they can be induced to differentiate into
cells with adipogenic and osteogenic lineages.31,34
Signaling by the wingless-type MMTV integration site family (WNT)-catenin pathway
seems to play a role in somatic stem-cell function in the myometrium and in uterine fibroid
tissue. Overall, total -catenin levels in the myometrium and fibroid tissue are similar.35 But
because the key effects of -catenin are probably
manifested at the level of stem cells, which make
up a very small fraction of fibroid or myometrial
tissue, differences in -catenin levels would not
be detected when whole fibroid and myometrial
tissues are compared. In mice, selective deletion
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of -catenin in uterine mesenchyme during embryonic development substantially reduces uterine size and replaces the uterus with adipocytes,
disrupting entirely the normal myometrial differentiation or regeneration of smooth muscle.
This observation suggests that -catenin plays a
key role in stem-cell renewal and in the differentiation of stem cells into the smooth-muscle
phenotype observed in myometrial and fibroid
tissues.29 Conversely, selective overexpression of
constitutively activated -catenin in uterine mesenchyme during embryonic development and in
adult mice gives rise to fibroidlike tumors in the
uterus.36
Complex mechanisms regulate the biologic
functions of -catenin. Secreted WNT proteins
bind to cell-surface receptors of the Frizzled
family, causing the activation of a cascade of
proteins that leads to decreased -catenin degradation in the cytosol and ultimately changes
the amount of -catenin that reaches the nucleus.37 Having escaped degradation, cytoplasmic
-catenin is able to enter the nucleus and interact with chromatin and the family of T-cell
transcription factor (TCF) proteins to regulate
the expression of a large number of genes and
alter key cellular functions, such as cell fate,
tumorigenesis, and differentiation.37 The size
and number of fibroidlike tumors driven by
-catenin increase with parity in mice, suggesting that ovarian hormones may interact with the
WNT-catenin pathway to accelerate tumorigenesis.36 The activated WNT-catenin pathway
has also been shown to stimulate the expression
of transforming growth factor 3 (TGF-3),
which induces cell proliferation and the formation of extracellular matrix in human fibroid
tissue.36,38 Fibroid-tissuederived TGF-3 may
also suppress the expression of local anticoagulant factors in adjacent endometrial cells, which
results in the prolonged menstrual bleeding associated with fibroids.7 These observations indicate that there are critical interactions among
activated WNT-catenin and TGF- pathways,
estrogen and progesterone, and stem-cell renewal and that these interactions ultimately give
rise to the clonal formation of uterine fibroid
tumors (Fig. 3).

GENE T IC FE AT UR E S
Hereditary syndromes and somatic chromosomal aberrations associated with uterine fibroids

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mechanisms of disease

Normal myometrium

Progesterone

Paracrine interactions induced

by estrogen or progesterone

CH3
CH3

CH3

Estrogen

Actively
dividing myometrial
cells

Myometrial
stem cell

OH

CH3

ER and PR

Mature
myometrial
smooth-muscle
cells

HO

Fibroid-tumor initiation

Paracrine interactions
induced by estrogen or
progesterone

Genetic hit

Progesterone

Estrogen

Actively
dividing fibroid
cells

Mutated myometrial
or fibroid stem
cell

Mature fibroid
smooth-muscle
cells

ER and PR

Fibroid-tumor growth
Paracrine interactions induced
by estrogen or progesterone

ER and PR
Actively
dividing fibroid
cells

Progesterone

Estrogen

Mutated myometrial
or fibroid stem
cell

Mature
myometrial
smooth-muscle
cells

Mature fibroid
smooth-muscle
cells

Fibroid-tissue
extracellular matrix

Figure 2. Tumorigenesis of Fibroids.

Both normal myometrial tissue and fibroid tissue contain pools of cells with the capacity for self-renewal; these populations are referred to as stem cells. A stem-cell population
responsible
for the proliferation of normal myometrial
C O L O R is
FIGU
RE
Draft 2 in part 9/10/2013
smooth-muscle cells (Panel A). This process accounts
for the physiologic enlargement of the uterus during
Bulun_ra1209993
pregnancy. Mature myometrial cells express Author
much higher
levels of estrogen receptor (ER) and progesterone re2abc
Fig #
ceptor (PR) than do stem cells. Thus, it is likely
that
estrogenUterine
Fibroids and progesterone-dependent cell proliferation is priTitle
Longo cells. Paracrine factors, such as WNT ligands, that are reDE in mature
marily mediated by the ER and PR that reside
Koopman
ME
leased by mature cells may act on stem cellsArtist
to induce
their self-renewal and proliferation. A genetic hit, such as a
Williams
Pub Date 10/3/2013
MED12 mutation or a chromosomal rearrangement
affecting HMGA2, may transform a myometrial stem cell into a
AUTHOR PLEASE
fibroid stem cell (Panel B). This fibroid cell may
self-renew
andNOTE:
start dividing in an uncontrolled fashion until it difFigure has been redrawn and type has been reset
check carefully
ferentiates into a mature fibroid smooth-muscle cell.Please
During
this process, fibroid smooth-muscle cells acquire many
epigenetic and phenotypic abnormalities. ERs and PRs are concentrated primarily in mature fibroid cells and pass
on estrogenic or progestogenic signals to stem cells through paracrine mechanisms. The single, transformed fibroid
stem cell eventually gives rise to a benign fibroid tumor with well-demarcated margins, which expands within the
myometrial tissue (Panel C). Extracellular-matrix formation contributes substantially to tumor expansion.

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TGF- receptor
expression
SMAD

WNT
ligands

Mature
myometrial or fibroid
smooth-muscle cell

Mutant
MED12

MAPK

Frizzled
receptors
-cateninTCF

ERPR

Proliferation

Mutant
MED12

-cateninTCF

Selfrenewal

Proliferation

Estrogen or
progesterone

TGF-

Selfrenewal

Fibroid stem
cell

Extracellular matrix
formation

Figure 3. Interactions among Ovarian Hormones, the -Catenin and TGF- Pathways, and MED12 in Fibroid Cells.
Since ER and PR levels are remarkably high in mature myometrial cells and fibroid cells as compared with stem
cells, estrogen and progesterone probably send signalsCOLOR
to fibroid
FIGURE stem cells through hormone receptors in mature
Draft 3 may increase
9/20/2013
cells in a paracrine fashion. Estrogen and progesterone
secretion of WNT ligands from mature smoothAuthor
muscle cells surrounding the stem cells. In both
cell Bulun_ra1209993
types, WNT, acting through the Frizzled family of receptors,
3
Fig #
activates the -cateninT-cell transcription factor
pathway,
which induces the production of transforming
Uterine
Fibroids
Title (TCF)
DE
growth factor (TGF-) in mature cells and leads
toLongo
excessive formation of extracellular matrix. In stem cells, nonME
mutant MED12 may act as a physiologic modifier
of Name
-catenin action, whereas mutant MED12 (or the absence of
Williams
Artist
MED12) may lead to the failure to accomplishPubthis
Date function.
10/3/2013 The absence of MED12 or the presence of the mutant
form in stem cells has also been linked to increased
expression
of the TGF- receptor, which leads to the activation
AUTHOR
PLEASE NOTE:
Figure has been redrawn and type has been reset
of its downstream signaling. This in turn activates thePlease
mothers
check carefullyagainst decapentaplegic homologue (SMAD) and
mitogen-activated protein kinase (MAPK) family proteins, mediating stem-cell self-renewal and proliferation.

have been reviewed previously.15,39 Analysis of

single-nucleotide polymorphisms in peripheralblood DNA has revealed three chromosomal loci
10q24.33, 22q13.1, and 11p15.5 associated
with uterine fibroids.40 Somatic mutations involving high-mobility group AT-hook 2 (HMGA2)
and MED12 are discussed here. Rearrangements
involving chromosome 12q14-15 are observed in
7.5% of fibroids. Most of the 12q15 breakpoints
are located upstream of the HMGA2 gene promoter, giving rise to full-length HMGA2 overexpression, and are strongly associated with large
fibroids.17 Hmga2 expression in murine neural
stem cells suppresses cyclin-dependent kinase
inhibitor 2a (Cdkn2a), which encodes the proteins p16Ink4a and p14Arf, negative regulators of
their self-renewal.41 In fibroid cells, HMGA2 appears to inhibit senescence by down-regulating
p14ARF.42 Intriguingly, uterine fibroids are deficient in the Let-7 miRNA that targets and sup1348

n engl j med 369;14

presses HMGA2.43 Thus, alterations in the Let7

HMGA2p14ARF pathway in fibroid stem cells
may favor self-renewal and offset senescence.
In their study of 225 fibroid tumors from 80
patients, Mkinen et al. found that approximately 70% contained heterozygous somatic mutations that affect MED12 on the X chromosome.19
The mutated allele was either predominantly or
exclusively expressed in affected tumors.44 Other
studies confirmed these findings and established that mutations in MED12 are also present
in small subsets of other mesenchymal tumors
of the uterus or in other tissues, although the
uterine fibroid remains the most frequently affected tumor.44-47
MED12 encodes a subunit of the mediator
complex, which consists of at least 26 subunits
and regulates transcription initiation and elongation by bridging regulatory elements in gene
promoters to the RNA polymerase II initiation

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mechanisms of disease

complex.19 The mediator complex is highly conserved in all eukaryotes and is required for the
transcription of almost all genes in yeast.48
MED12, together with MED13, cyclin-dependent
kinase 8 (CDK8), and cyclin C, also forms a mediator subcomplex (the CDK8 module) that regulates transcription.48 MED12 binds directly to
-catenin and regulates canonical WNT signaling.49 Because MED12 limits -catenindependent tissue growth during embryonic development, a critical question is whether the absence
of MED12 or the presence of a defective version
in uterine fibroid stem cells or the main fibroidcell population causes -catenin pathwaydependent tumor growth.50,51 The expression of WNT4,
an activator of -catenin, is markedly elevated in
fibroids with MED12 mutations as compared
with those without these mutations (Fig. 3).47
In a further twist, MED12 deficiency activates
the TGF- pathway, leading to drug resistance
and fibroid-cell proliferation mediated by members of two signaling protein families in cancer
cells: the mothers against decapentaplegic homologue (SMAD) and mitogen-activated protein
kinase (MAPK) (Fig. 3).52 It is postulated that
MED12 deficiency in somatic stem cells may
trigger these events.48 These observations point
to a mechanism involving MED12 mutations,
WNT-catenin activation, and hyperactive TGF-
signaling that supports stem-cell renewal, cell
proliferation, and fibrosis in uterine fibroid tissue (Fig. 3).48,53,54

EPIGENE T IC FE AT UR E S
Epigenetic mechanisms such as DNA methylation and histone modification may be inherited
and may regulate gene expression independently
of the primary DNA sequence. DNA methyltransferases catalyze the covalent addition of a methyl
group to a cytosine in a cytosineguanine sequence. As the degree of methylation of cytosineguanine sequences in a gene promoter increases, its expression decreases. This mechanism
is particularly important for differential gene expression in stem cells.55-57
The aberrant expression of specific DNA
methyltransferases in uterine fibroid tissue as
compared with normal myometrial tissue prompted further research into DNA methylation in
these tumors.58 Genomewide profiling of DNA
methylation and messenger RNA (mRNA) ex-

pression in uterine fibroid tissue and matched

normal myometrial tissue from 18 black women
revealed 55 genes in the two tissue types in
which there were differences affecting promoter
methylation and mRNA transcription.20 The majority of these genes (62%) displayed hypermethylation at promoter sites that were associated
with their silencing in the fibroid tissues.20 A
large number of tumor suppressors, including
the gene encoding the transcription factor Krppel-like factor 11 (KLF11), were among these
hypermethylated and repressed genes.20 KLF11,
also a target of progesterone or antiprogestins in
uterine fibroid tissue, probably plays a distinct
role in the fibroid development.20,59 These observations point to the important contribution of
promoter methylation-mediated gene silencing
in the pathogenesis of uterine fibroids.

E S T RO GEN
A large body of experimental data and circumstantial evidence suggests that estrogen stimulates the growth of uterine fibroids through estrogen receptor .60 The primary roles of estrogen
and estrogen receptor in fibroid growth are
permissive in that they enable tissue to respond
to progesterone by inducing the expression of
progesterone receptor (Fig. 4).10 Fibroid tissue is
exposed to ovarian estrogen and to estrogen produced locally through the aromatase activity in
fibroid cells.61
In fibroid tissue, multiple promoters controlled by a diverse set of transcription factors
contribute to the expression of a single aromatase protein that converts circulating precursors
into estrogens.62 The mechanism underlying
gonadotropin-independent expression of aromatase in fibroid tissue is not completely understood.63 It is likely that local aromatase activity
in fibroids is clinically relevant because fibroid tissue from black women who have an increased
prevalence of uterine fibroids and an earlier age
at diagnosis, as compared with white women
contain high levels of aromatase, which result
in elevated levels of estrogen in tissue.64,65 Most
important, aromatase inhibitors are as effective
as GnRH analogues in shrinking fibroid volume,
despite stable levels of circulating estrogen.
These observations suggest that the inhibition of
aromatase in fibroid tissue is a key mechanism
in hormone-dependent fibroid growth (Fig. 4).66

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Adrenal gland
Skin and
adipose tissue

Ovary

Estrogen, androstenedione, and

progesterone in circulation

Fibroid tissue
CH3
CH3
CH3

N
H3C

CH3

CH3

Aromatase
inhibitor

Antiprogestin

Progesterone

OH

CH3

OH

Proliferation
O

HO

Androstenedione

Aromatase

PR

ER

Estradiol

Apoptosis
Extracellular matrix
formation
Tumor growth

Figure 4. Biologic Effects of Estrogen and Progesterone on Fibroid Tissue.

In peripheral tissues (skin and adipose tissue) and the ovaries, aromatase catalyzes the formation of estrogen,
which reaches uterine fibroid tissue through the circulation. In addition, aromatase in fibroid tissue converts androCOLOR FIGURE
stenedione of adrenal or ovarian origin to estrogen locally.
The biologically potent estrogen, estradiol, induces the
Draft 3
9/12/2013
production of PR by means of ER. PR is essential
for
the
response
of fibroid tissue to progesterone secreted by the
Author
Bulun_ra1209993
ovaries. Progesterone and PR are indispensible
to
tumor
growth,
increasing cell proliferation and survival and en4
Fig #
Uterine
hancing extracellular-matrix formation. In theTitleabsence
of Fibroids
progesterone and PR, estrogen and ER are not sufficient
DE
for fibroid growth. Immunohistochemical staining
inLongo
fibroid tissue (insets, brown) indicates nuclear localization of
Name
ME
ER or PR in smooth-muscle cells. The fact Artist
that an Williams
aromatase inhibitor or antiprogestin shrinks fibroid tumors proDate 10/3/2013
vides support for this mechanism of fibroid Pub
growth.
AUTHOR PLEASE NOTE:

Figure has been redrawn and type has been reset

Please check carefully

PRO GE S TERONE
An in vivo model in which human fibroid tissue
was grafted under the kidney capsule in mice revealed that progesterone and its receptor were
essential and sufficient for tumor growth, as in1350

n engl j med 369;14

dicated by the stimulation of cell proliferation,

the accumulation of extracellular matrix, and
cellular hypertrophy.10 A number of clinical observations also support these findings. The use
of progestins in hormone-replacement regimens
stimulates the growth of fibroids in postmeno-

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mechanisms of disease

pausal women in a dose-dependent manner, and

the addition of progestins to GnRH agonists diminishes the inhibitory effects of these agonists
on leiomyoma size.67,68 The strongest evidence
supporting the in vivo growth-stimulating effects of progesterone on fibroids comes from
clinical trials of three different antiprogestins,
each of which showed that treatment consistently reduced tumor size (Fig. 4).69-72
Progesterone receptor, a ligand-activated
transcription factor, mediates the actions of progesterone and antiprogestins and exerts broad
biologic effects as a master regulator of hundreds of genes at any given time (Fig. 5).73
Across the genome of fibroid smooth-muscle
cells, the antiprogestin RU486bound progesterone receptor interacts with more than 7000 DNA
sites, most of which lie very far from transcription start sites.74 More than 75% of RU486-regulated genes contain a progesterone-receptor
binding site that is more than 50,000 bp from
their transcription start sites; these genes control cell growth, focal adhesion, and the functioning of the extracellular matrix.74 This mechanism, in which genes are regulated by the
progesterone receptor, contrasts with that seen
in breast-cancer cells, in which the majority of
genomic targets of the RU486-bound progesterone receptor reside within 5000 bp of a regulated gene.74 These observations underscore the
complexity of progesterone and antiprogestin
action and account for the difficulties in identifying a single progesterone-receptor target gene
for use as an effective therapeutic strategy.
In fibroid cells, the antiprogestin RU486bound progesterone receptor assembles a transcriptional complex that forms a bridge between
a 20,500-bp distal DNA sequence and the transcription start site of the tumor-suppressor gene
KLF11, leading to an increase in gene expression
and protein levels (Fig. 5).59 Once encoded,
KLF11 effectively inhibits the proliferation of
fibroid cells.59 In contrast, progesterone-bound
progesterone receptor maintains transcriptional
repression of KLF11 through the same regulatory
DNA sequence; this transcriptional control occurs in addition to the epigenetic mechanism
discussed above (i.e., hypermethylation of the
KLF11 transcription start site).20,59 Progesterone,
on the other hand, increases the level of the
antiapoptotic protein BCL2 through the binding
of progesterone receptor to a classical sequence

immediately upstream of the BCL2 transcription

start site, thereby inhibiting cell death in fibroid
tissue (Fig. 5).75
In addition to the direct transcriptional effects mediated by nuclear progesterone receptor,
the binding of progesterone to cytoplasmic progesterone receptors can rapidly activate the extranuclear phosphatidylinositol 3-kinaseAKT
signaling pathway in uterine fibroid cells.76 Consequently, treatment of leiomyoma cells with an
AKT inhibitor reduces progesterone-induced
proliferation and survival of fibroid cells, underscoring the capacity of the progesterone receptor
to interact with cytoplasmic signaling pathways.76
During pregnancy, progesterone and its receptor are instrumental in the physiologic
growth of myometrial tissue, which after delivery regresses almost to its original volume. This
fact argues against the view that progesterone
receptor exerts a primary tumor-initiating action. However, by signaling through its receptor,
progesterone may play a central role in the
clonal expansion of genetically or epigenetically
altered fibroid stem cells into clinically detectable fibroids, and it may further the growth of
these tumors by affecting both stem cells and
differentiated fibroid cells.31 Since the stem-cell
population expresses much lower levels of progesterone receptor than the population of mature cells but serves as the key source of tissue
growth, a paracrine signal originating from
progesterone-receptorrich differentiated cells
may mediate the proliferative effects of progesterone on fibroid stem cells (Fig. 2).33,34

SUM M A R Y
During a womans reproductive years, myometrial smooth-muscle cells undergo multiple cycles of growth followed by involution under the
influence of ovarian hormones or the hormones
of pregnancy. These cycles make stem cells vulnerable to the development of mutations. A point
mutation affecting the function of MED12, a
chromosomal rearrangement increasing the expression of HMGA2, or some other gene defect in
a somatic stem cell in the myometrium may be
the initiating event of tumorigenesis. This original, single genetic hit may alter key signaling
pathways such as those involving -catenin and
TGF-, which regulate cell proliferation, survival, and senescence and the formation of extracel-

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Genomewide binding of progesterone and the antiprogestin RU486

CH3

Progesterone

CH3
CH3

Antiprogestin RU486

N
H3C

CH3

PR

CH3

OH

CH3

H
H
O

10

11

12

X
13

14

15

16

17

18

19

20

21

22

PR interaction sites
Antiprogestin
RU486

PR

Progesterone
PR

PR

2 0 ,
Coregulators
MED12 ?

PR

PR

MED12 ?
RNA
polymerase II

553 bp PRE 539 bp

BCL2
Apoptosis

PR

bp

SP1
SR C

SP1
+1

50 0

RNA
polymerase II

KLF11

Tumor growth

Proliferation

+1

Tumor growth

lular matrix, leading to clonal expansion

of9/12/2013
the or chromosomal rearrangement and an abnorDraft 3
stem cells within the genetically
normal
myome- mal epigenetic signature favoring further growth.
Author
Bulun_ra1209993
5ab
trium. The majority of the cellsFig
in# this
expanding
In this context, the inherent capability of
Uterine Fibroids
Title
DE
clone will differentiate and develop
aLongo
phenotype myometrial tissue to respond to estrogen and
Name
ME
similar to that of myometrial
progesterone for physiologic expansion during
Williams
Artist smooth-muscle
Pub Date 10/3/2013
cells but will also maintain the original mutation the luteal phase of the ovulatory cycle or pregCOLOR FIGURE

AUTHOR PLEASE NOTE:

Figure has been redrawn and type has been reset

Please check carefully

1352

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mechanisms of disease

Figure 5 (facing page). Mechanisms of Progesterone

and Antiprogestin Action in Fibroid Cells.
Panel A shows the genomewide binding of PR (blue
circles), which is bound by progesterone or the antiprogestin RU486. Each ligand acts as a principal regu
lator of gene expression and exerts broad biologic effects by inducing the binding of PR to thousands of
sites across the genome and altering the expression
ofhundreds of genes at a time. The distribution of PRbinding sites across chromosomes (1 to 22 and X) is
highly correlated with chromosome length and with
the number of transcription start sites of genes in an
individual chromosome. Panel B shows two target
genes of PR, BCL2 and KLF11; each has distinct promoter contexts. Progesterone induces the binding of
PR as a homodimer to a classical progesterone response element (PRE) that lies approximately 500 bp
upstream of the transcription start site (+1) of BCL2.
This action enhances transcription by means of both
unknown coregulators and RNA polymerase II, leading
to increased levels of BCL2, which in turn reduce apoptosis and promote tumor growth. The antiprogestin
RU486 inhibits BCL2 expression. The promoter region
of another PR target, KLF11, a tumor-suppressor gene,
lacks a classical PRE. The antiprogestin RU486 enhances PR binding to a site 20,500 bp upstream of the promoter region of KLF11. RU486-bound PR assembles an
enhancer transcriptional complex containing specificity
protein 1 (SP1), steroid receptor coactivator 2 (SRC2),
and RNA polymerase II all of which interact with both
the transcription start site and the PR binding site. When
RU486 is added to fibroid cells, it induces the production of KLF11, which suppresses cell proliferation and
tumor growth. Progesterone inhibits KLF11 expression.
The effects of the ubiquitous transcriptional regulator
MED12 on these promoters are not known.

nancy may work to the advantage of fibroidtumor growth. Such growth may be mediated by
high levels of estrogen and progesterone receptors in normal myometrial cells or by the differentiated population of fibroid cells that send
paracrine signals to the receptor-deficient fibroid stem cells for self-renewal. For unknown
reasons, most uterine fibroids do not acquire
further critical genetic hits and therefore remain
benign. Many diverse molecular and cellular
abnormalities may give rise to a uterine fibroid,
an extraordinarily common phenotype. Thus, depending on their genetic and epigenetic makeup
and the nature of the surrounding molecular and
endocrine environment, these tumors vary in
their potential for massive further growth, dormancy, and regression. The diverse mechanisms
that favor tumorigenesis and the growth of uterine fibroids also provide the basis for their heterogeneous response to medical therapy.
A class of antiprogestins currently represents
the most specific medical approach to targeting
a defined mechanism in fibroids (Fig. 4).69-72 In
fact, antiprogestins induce amenorrhea and reduce tumor size in the majority of treated patients.71,72 Targeting of pathways involving fibroid stem cells that primarily control tumor
growth should lead to the development of new
treatments.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.

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