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REVIEW

Molecular pathology of endometrial carcinoma


Xavier Matias-Guiu
1
& Jaime Prat
2
1
Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova,
University of Lleida, IRBLLEIDA, Lleida, and
2
Department of Pathology, Hospital de la Santa Creu i Sant Pau, Institut
dInvestigacio Biomedica (IIB) Sant Pau, Autonomous University of Barcelona, Barcelona, Spain
Matias-Guiu X, & Prat J
(2013) Histopathology 62, 111123
Molecular pathology of endometrial carcinoma
This review paper discusses the main molecular alter-
ations of endometrial carcinoma, the most common
cancer of the female genital tract. Two clinicopatho-
logical variants are recognized: the oestrogen-related
(type I, endometrioid carcinoma) and the non-oestro-
gen-related (type II, non-endometrioid carcinoma).
Whereas type I shows microsatellite instability and
mutations in PTEN, PIK3CA, K-RAS and CTNNB1
(beta-catenin), type II exhibits TP53 mutations and
chromosomal instability. Recent investigations
regarding the role of non-coding RNA have provided
important information regarding tumour progression.
Understanding pathogenesis at the molecular level is
essential for identifying biomarkers of potential use in
targeted therapies.
Keywords: apoptosis, beta-catenin, chromosomal instability, E-cadherin, endometrial carcinoma, K-RAS,
microsatellite instability, molecular genetics, PTEN, PIK3CA, TP53
Molecular features of endometrial
carcinoma
In western countries, endometrial carcinoma (EC) is
the most common malignant tumour of the female
genital tract, accounting for 1020 per 100 000 per-
son-years. From a pathogenetic viewpoint, EC falls
into two different types, i.e. types I and II.
1
Type I
tumours are low-grade oestrogen-related endometri-
oid carcinomas (EEC) that usually develop in peri-
menopausal women and coexist with or are preceded
by complex and atypical endometrial hyperplasia
(Figure 1A). In contrast, type II tumours are aggres-
sive non-endometrioid carcinomas (NEEC) (mainly
serous and clear cell carcinomas) that occur mainly
in older women and are unrelated to oestrogen stim-
ulation (Figure 1B). Occasionally, type II carcinomas
may arise in association with so-called serous endo-
metrial intraepithelial carcinoma, either from atro-
phic endometrium or endometrial polyps. It has been
shown that the molecular alterations involved in the
development of EEC (type I) carcinomas differ from
those of NEEC (type II) carcinomas.
24
EEC shows mi-
crosatellite instability (MI) and mutations in the
PTEN, K-RAS, PIK3CA and CTNNB1 (beta-catenin)
genes, whereas NEEC exhibit alterations of p53, loss
of heterozygosity (LOH) on several chromosomes, as
well as other molecular alterations (STK15, p16,
E-cadherin and c-erb-B2).
MI has been demonstrated in 75% of EC associated
with hereditary non-polyposis colon cancer (HNPCC),
but also in 2530% of sporadic EC
59
(Figure 2). In
sporadic EC, MI occurs more frequently in EEC (30%)
than in NEEC, and is secondary to MLH-1 promoter
hypermethylation. Although data are controversial
regarding the prognostic signicance of MI, it is usu-
ally associated with a high histological grade. The
MI-associated mismatch repair deciency leads to the
accumulation of many mutations in coding and non-
coding DNA sequences, including short-tandem
repeats, named microsatellites. Some small short-tan-
Address for correspondence: X Matias-Guiu, Department of
Pathology and Molecular Genetics, Hospital Universitari Arnau de
Vilanova, Av. Alcalde Rovira Roure 80, 25198 Lleida, Spain.
e-mail: xmatias@arnau.scs.es
2012 Blackwell Publishing Limited.
Histopathology 2013, 62, 111123. DOI: 10.1111/his.12053
dem repeats, such as mononucleotide repeats, are
located within the coding sequence of some impor-
tant genes (BAX, IGFIIR, hMSH3, hMSH6, MBD4,
CHK-1, Caspase-5, ATR, ATM, BML, RAD-50, BCL-10
and Apaf-1) (Figure 3), and they may be potential
targets in the process of tumour progression of MI
+
,
EC.
10,11
PTEN, located on chromosome 10q23.3, is fre-
quently abnormal in EC.
1216
LOH at the PTEN
region occurs in 40% of EC. Somatic PTEN mutations
are also common and found predominantly in EEC,
occurring in 3761% of cases (Figure 4). PTEN muta-
tions are found in 6086% of MI-positive EEC, but in
only 2435% of the MI-negative tumours. Identical
PTEN mutations have been detected in hyperplasias
coexisting with MI-positive EEC, which suggests that
PTEN mutations are early events in tumour
development. Although data regarding the prognostic
A
B
Figure 1. A, Endometrioid carcinoma. Upper left: Polypoid tumour with only supercial myometrial invasion. Upper right:
Well-differentiated (grade 1) adenocarcinoma. B, Non-endometrioid carcinoma. Lower left: large haemorrhagic and necrotic tumour
with deep myometrial invasion; lower right: serous carcinoma (grade 3) exhibiting stratication of anaplastic tumour cells and abnormal
mitoses.
Microsatellite instability (MSI)
Hereditary non-polyposis colorectal carcinoma (HNPCC)
Sporadic cancers: colon, stomach, pancreas, ovary and
endometrium
MSH2
MSH2
MSH6
MSH6
PMS2
PMS2
TUMOR
TUMOR
(Mutations)
n
Inactivation by promoter
hypermethylation
MLH1
MLH1
MLH1
Figure 2. Microsatellite instability in hereditary and sporadic
endometrial carcinoma.
2012 Blackwell Publishing Ltd., Histopathology, 62, 111123.
112 X Matias-Guiu & J Prat
signicance of PTEN mutations in EC are controver-
sial, some results suggest an association with favour-
able prognostic factors. Several studies have shown
that EECs with PTEN mutations have genomic
instability. For this reason, some authors suggest
treating patients with poly (ADP- ribose) polymerase
(PARP) inhibitors.
Mutations in PIK3CA contribute to alteration of the
PI3KAKT signalling pathway in EC.
1724
PI3K (phos-
phatidylinositol 3-kinase) is a heterodimeric enzyme
consisting of a catalytic subunit (p110) and a regula-
tory subunit (p85). The PIK3CA gene, located on chro-
mosome 3q26.32, codes for the p110a catalytic
subunit of PI3K. A high frequency of mutations in the
PIK3CA gene has been reported recently in EC. Muta-
tions are located predominantly in the helical (exon 9)
and kinase (exon 20) domains, but they can also occur
in exons 17. PIK3CA mutations occur in 2439% of
the cases, and coexist frequently with PTEN mutations
(Figure 5). PIK3CA mutations, particularly in exon 20,
have been associated with adverse prognostic factors
such as high histological grade and myometrial inva-
sion. Although described initially in EEC, PI3KCA
mutations also occur in NEEC and mixed EECNEEC.
Furthermore, different gene expression proles in the
PI3KAKT signalling pathway serve to separate two
subgroups of high-grade EC with distinct molecular
alterations (PI3KAKT pathway versus p53
alterations) that may play different roles in endometrial
MSP
Bat-25 Bat-26
MLH1 promoter
hypermethylation
Loss of
MLH1
expression
MI
BAX
BAX
T1
T1
T2
T2
IGFIIR
MSH3
PTEN
Casp-5
Bcl-10
APAF-1
U U M M
N
T
N+T
Figure 3. MLH1 inactivation by promoter hypermethylation is the most common cause of the microsatellite instability (MI) phenotype in
endometrial carcinoma. Progressive accumulation of alterations secondary to MI affects important regulatory genes and promotes
carcinogenesis. BAX somatic frameshift mutations are distributed heterogeneously throughout the tumour and provide selective growth
advantage. T1: BAX-non-mutated component of endometrioid endometrial carcinoma; T2: BAX-mutated component of endometrioid
endometrial carcinoma. MSP: methylation specic PCR, U: unmethylated DNA, M: methylated DNA. N: normal tissue, T: tumour tissue.
Tumour in the histological section on the left failed to react with anti-MLH-1 antibody, demonstrating negative immunoreaction in tumour
cells with MLH-1 promoter hypermethylation. The section on the right was incubated with an antibody against the carboxy-terminus of
BAX. The negative area (T2) corresponds to tumour cells having mutations in the mononucleotide tract of BAX, which is typical of
endometrial carcinomas with MI.
PTEN
MUTATION
PROMOTER
HYPERMETHYLATION
LOH
T
N
76 79 82 85 88
Figure 4. Inactivation of tumor suppressor gene PTEN may occur
by several mechanisms such as point mutation, promoter
hypermethylation, or deletion (loss of heterozygosity [LOH]) at
10q23. T: tumour DNA, N: normal tissue DNA.
2012 Blackwell Publishing Ltd., Histopathology, 62, 111123.
Endometrial carcinoma 113
carcinogenesis
24
(Figure 6). Moreover, mutations in
PIK3RI, the gene encoding p85a, the inhibitory sub-
unit of PI3K, have been detected in 43% of EEC and
12% of NEEC.
The RAS-RAF-MEK-ERK signalling pathway plays
an important role in tumorigenesis. The frequency of
K-RAS mutation in EC ranges between 10 and 30%. In
some series, K-RAS mutations have been reported to be
more frequent in EEC showing MI.
25
BRAF, another
member of the RASRAFMEKERK pathways, is
mutated very infrequently in EC.
26
RAS effectors such
as RASSF1A are thought to provide an inhibitory
growth signal, which needs to be inactivated during
tumorigenesis. RASSF1A inactivation by promoter
hypermethylation may contribute signicantly to
increased activity of the RASRAFMEKERK signal-
ling pathway.
27
PIP
2
Dephosphorylation
Phosphorylation
PIP
3
P
PTEN P13K
ATP
ADP
AKT-P
Cell proliferation and survival
Figure 5. Phosphatidylinositol 3-kinase (PI3K)PTEN function.
Phosphorylation by PI3K converts phosphatidylinositol
biphosphate (PIP2) into phosphatidylinositol triphosphate (PIP3),
promoting cell proliferation and survival. PTEN regulates PI3K
signalling negatively by dephosphorylation of PIP3.
P21
AKT1
FAK
PAK1
CCND1
FAS
FOXO1A
P27
P53
XIAP
NFKB
GSK3B
mTOR
E-CADH
CASP3
PIK3CA
AKT2
MDM2
PTEN
p53 alterations
PIK3CA exon 20 mutations
PIK3CA exon 9 mutations
PTEN mutations
MI
High-grade
High-stage
>50% myometrial infiltration
Vascular invasion
Yes No Not assessed
Cluster 3
U
p
r
e
g
u
l
a
t
i
o
n
D
o
w
n
r
e
g
u
l
a
t
i
o
n
Cluster 2 Cluster 1
Non-endometrioid
p16 overexpression
Figure 6. Hierarchical clustering analysis of mRNA expression of 19 genes in 38 endometrial carcinomas. Up-regulated and down-regulated
expression are indicated as red and green cubes, respectively. Genes that did not vary in their expression level are shown in black, and
genes with unsatisfactory results labelled in grey. Enclosed in the clustering image, results of p53, p16, PIK3CA, PTEN and microsatellite
instability (MI) analysis, as well as clinicopathological parameters such as high-grade (grade 3), non-endometrioid, high-stage (stage 2 or
higher), myometrial invasion (>50%) and vascular invasion, are represented graphically for each case.
2012 Blackwell Publishing Ltd., Histopathology, 62, 111123.
114 X Matias-Guiu & J Prat
Several studies suggest that the broblast growth
factor (FGF) signalling pathway is important in EC. It
has been shown that EC presents frequent inactiva-
tion of SPRY-2, a protein involved in the negative
regulation of the FGF receptor (FGFR) pathway by
promoter methylation.
28
Reduced SPRY2 immunoex-
pression is seen in almost 20% of EC and is associated
strongly with increased cell proliferation. Moreover,
somatic mutations in the receptor tyrosine kinase
FGFR2 have been detected recently in 612% of EC,
particularly in EEC.
2931
Interestingly, FGFR2 muta-
tions and K-RAS mutations are mutually exclusive
events, while mutations in FGFR2 and PTEN fre-
quently coexist. FGFR2 is of special interest as a
potential target therapy, and FGFR-2 inhibitors are
currently under consideration.
The beta-catenin gene (CTNNB1) maps to 3p21.
Beta-catenin is a component of the E-cadherincatenin
unit, which plays an important role in cell differentiation
and maintenance of normal tissue architecture. Muta-
tions in exon 3 of CTNNB1 result in stabilization of the
beta-catenin protein, cytoplasmic and nuclear accu-
mulation, and participation in signal transduction and
transcriptional activation through the formation of
complexes with DNA binding proteins (Figure 7).
Mutations in exon 3 of CTNNB1 with nuclear accumu-
lation of beta-catenin occur in 1444% of EC.
3136
Alterations in CTNNB1 have been described in endome-
trial hyperplasias that contain squamous metaplasia
(morules). Although data are controversial regarding
the prognostic signicance of CTNNB1 mutations in EC,
they probably occur in tumours associated with a good
prognosis.
In contrast to EEC, NEEC show TP53 mutations
(90%), markedly reduced expression of E-cadherin
(8090%), c-erb-B2 (HER-2) amplication (30%),
alterations in genes involved in regulation of the
mitotic spindle checkpoint (STK15) and loss of hetero-
zygosity at multiple loci reecting chromosomal insta-
bility. While TP53 mutations occur in 90% of NEEC,
they are present in only 1020% of EEC (Figure 8),
mainly grade 3 tumours.
3739
Reduced expression of
CTNNB1
Codon 37
TCT CCT
Ser Pro
Exon 3
Figure 7. Upper left, CTNNB1 (beta-catenin gene) mutations shown by single-strand conformation polymorphism (SSCP) analysis with
abnormal extra band; and upper right, corresponding partial representative nucleotide sequence demonstrating a missense mutation in exon
3. Different patterns of beta-catenin immunostaining in endometrioid carcinoma: lower left, membranous immunoreaction; lower middle,
membranous immunostaining with occasional positive nuclei; and lower right, membranous and nuclear immunostaining in squamous
morules. The latter two indicate aberrant protein expression and are associated with CTNNB1 mutation.
2012 Blackwell Publishing Ltd., Histopathology, 62, 111123.
Endometrial carcinoma 115
E-cadherin is frequent in EC, and may be caused by
LOH or promoter hypermethylation. In fact, LOH at
16q22.1 is seen in almost 60% of NEEC, but in only
22% of EEC. C-erb-B2 overexpression and amplica-
tion are also seen more frequently in NEEC (43% and
29%, respectively) than in EEC.
40
However, the most
typical molecular feature of NEEC is the presence of
widespread chromosomal gains and losses which
reect the presence of aneuploidy.
41
cDNA arrays
have demonstrated that NEEC usually show up-regu-
lation of genes (STK15, BUB1, CCNB2) involved in
the regulation of the mitotic spindle checkpoint. One
of these genes, STK15, essential for chromosome seg-
regation and centrosome functions, is amplied fre-
quently in NEEC. Recently documented potential
biomarkers of serous carcinoma are epithelial cell
adhesion molecule (EpCAM), claudin-3 and claudin-4
receptors, serum amyloid A, folate binding protein,
mesothelin and insulin-like growth factor-II mRNA
binding protein 2 (IMP2).
Among NEEC, clear cell carcinomas show specic
features. Endometrial clear cell carcinomas appear to
represent a heterogeneous group of tumours that may
arise through different pathogenetic pathways. Based
on morphological similarities between ovarian and
endometrial clear cell carcinomas, it has been sug-
gested that both tumour types may exhibit similar
alterations, including mutations in PIK3CA and PTEN.
Mutation of the ARID1A gene and loss of the corre-
sponding protein BAF250a have been described as fre-
quent events in clear cell and endometrioid carcinomas
of the ovary. In a recent study, however, these changes
have been found in 29% of grades 1 or 2 and 39% of
grade 3 EECs, 18% of serous NEEC and 26% of clear
cell NEEC. Uterine low-grade endometrioid carcinomas
have also shown loss of ARID1A expression (26%) and
ARID1A mutations (40%).
42,43
cDNA array studies have shown that the expres-
sion proling of EEC differs from that of NEEC.
4447
Genes up-regulated in serous carcinomas were
IGF2, PTGS1, FOLR and p16, whereas genes up-reg-
ulated in EEC included TFF3, FOXA2 and MSX2.
Moreover, two members of the secreted frizzled
related protein family (SFRP1 and SFRP4) were
down-regulated more frequently in EC with MI.
48
Interestingly, by comparing the expression proles
of similar histological subtypes of ovarian and endo-
metrial carcinomas it was found that clear cell
carcinomas had a similar prole, regardless of the
organ of origin. In contrast, differences were strik-
ing between endometrioid and serous carcinomas of
ovarian and endometrial origin.
Classication of EC into two groups (types I and II) is
articial and too rigid, and the dualistic model has
been challenged recently. In daily practice, pathologists
are faced with tumours showing mixed, combined or
hybrid morphological and molecular characteristics
(often endometrioid and serous carcinomas). Further-
more, though serous and clear cell carcinomas have
been classied within the same category of NEEC, based
mainly on their common high nuclear grade and
aggressive behaviour, recent studies have shown that
these carcinomas are, in fact, distinct tumour types
exhibiting different clinical, immunohistochemical and
molecular features. Based on molecular analyses, it has
been suggested that in mixed EECNEEC the NEEC
component originates from a pre-existing EEC as a
result of tumour progression and, not infrequently,
these tumours retain their typical EEC molecular alter-
ations (Figure 9). This hypothesis would explain the
existence of mixed EECNEEC, the presence of MI and
the alterations in PTEN, K-RAS or beta-catenin in some
cases of NEEC. Another controversial scenario is the
grey zone between high-grade (predominantly solid)
PTEN
MI
B-Catenin
K-Ras
PIK3CA
Exon 9
Exon 20
Exon 20
EEC Low-grade EEC High-grade Mixed EEC - NEEC NEEC
mRNA overexpression
P53
Figure 8. Microsatellite instability (MI) and PTEN, PIK3CA, K-RAS, CTNNB1 (beta-catenin) and TP53 mutations are the most common
molecular genetic alterations in endometrial carcinomas. EEC: endometrioid endometrial carcinoma; NEEC: non-endometrioid endometrial
carcinoma.
2012 Blackwell Publishing Ltd., Histopathology, 62, 111123.
116 X Matias-Guiu & J Prat
EEC and NECC. Distinction between these two types of
tumours is difcult; conversely, high-grade EEC occa-
sionally exhibit molecular alterations typical of NEEC
such as TP53 mutations.
Undifferentiated carcinomas of the endometrium
are epithelial tumours that fail to show evidence of
either glandular or squamous differentiation. They
represent 110% of EC, and show a proliferation of
medium-sized, monotonous, epithelial cells growing
in solid sheets. Occasionally, undifferentiated carcino-
mas arise from pre-existing well- or moderately-differ-
entiated EEC. The term de-differentiated carcinoma
has been used to designate such special tumour types.
Several groups of investigators have conrmed that
MI is the predominant molecular feature encountered
in this type of carcinoma.
49
However, MI is not seen
in all cases, and some tumours may have TP53
mutations suggesting transformation into a high-
grade carcinoma.
Malignant mixed m ullerian tumours (MMMT), also
referred to as uterine carcinosarcomas or sarcomatoid
carcinomas, are rare uterine tumours accounting for
less than 5% of EC. Molecular studies have suggested
recently that MMMT should be regarded as metaplastic
carcinomas. Like sarcomatoid carcinomas of other
locations, carcinosarcomas probably result from endo-
metrial carcinomas through epithelial-to-mesenchymal
transition (EMT). EMT is a process of cellular transdif-
ferentiation in which epithelial cells lose polarity and
cellcell contacts, reorganize their cytoskeleton,
acquire expression of mesenchymal markers and mani-
fest a migratory phenotype. EMT can be induced by
different signals and pathways, such as those medi-
ated by transforming growth factor (TGF)-b, tyrosine
kinase receptors and/or Wnt, depending on the spe-
cic cellular context. Activation of one or more of
these pathways converges frequently in a group of
transcription factors, Snail1, Slug, ZEB1, ZEB2, E47,
E2-2 and Twist, most of them with the ability to
repress E-cadherin, a master regulator of cell adhe-
sion and polarity. While the transient presence of
EMT features is important for myometrial invasion
in conventional endometrial carcinomas, MMMT
show permanent expression of these features leading
to repression of epithelial markers (E-cadherin) and
increased expression of mesenchymal markers,
including proteins involved in skeletal muscle devel-
opment. All these molecular changes are responsible
for the appearance of the sarcomatous areas as well
as the presence of heterologous elements. It has
been shown recently that MMMT show a microRNA
signature typical of EMT.
50
Non-coding RNA
The classic perception that cancer resulted mainly
from alterations in coding genes has been challenged
recently by demonstration of the important roles of
non-coding RNAs, such as microRNA and long non-
coding RNA (lncRNA).
M I C R O R N A
MicroRNAs (miRNAs) are small, approximately 20-
nucleotide-long, non-coding single-stranded RNA
molecules regulating the expression of target genes
by imperfect (in animals) binding to the 3-untrans-
lated region (UTR) and possibly 5-UTR of mRNA. To
become the mature form, miRNAs are processed by
enzymatic complexes Dorsha and Dicer, and they
repress translation or lead to the degradation of the
mRNA of their target genes. Currently approximately
2000 human miRNA sequences have been identied,
and this number continues to grow. Regardless of the
relatively small number of miRNAs, as each single
miRNA targets several hundred genes, and a single
target gene can bind to multiple miRNAs, thus mak-
ing the whole network very complex, it is believed
that approximately 30% of all human genes are a
target for miRNA regulation. There is also evidence
that these small molecules are expressed in a tissue-/
cell-specic manner, being reserved restrictively to
specic cell type or associated ubiquitously with dif-
ferent human body compartments. It was shown pre-
viously that dysfunctional expression of miRNAs is a
MI
PTEN
KRAS
beta-catenin
PIK3CA (9,20)
Tumor
progression
Gene alterations
PIK3CA (20)
P53
NE
Low-grade
Endometrioid Ca
Non-Endometrioid Ca
High-grade
Endometrioid Ca
PIK3CA (20)
Cadherin E
Cyclic D1
Cyclic E
Her-2/neu
STK15
Figure 9. Pathogenesis of endometrial carcinoma: an alternative to
the dualistic model. Exons 9 and 20 of PIK3CA are those
frequently mutated in endometrial carcinoma. Ca: carcinoma; NE:
normal endometrium.
2012 Blackwell Publishing Ltd., Histopathology, 62, 111123.
Endometrial carcinoma 117
frequent attribute of malignant behaviour. Nowadays,
aberrant expression of specic miRNAs is associated
with all cancer types. Germline and somatic muta-
tions as well as polymorphisms in the mRNAs tar-
geted by miRNAs can also lead to cancer
predisposition and progression. Growing evidence
points to miRNA being implicated in oncogenic pro-
cesses, suggesting that miRNA expression proling
can distinguish tumours (according to diagnosis and
cancer stages) more accurately than traditional gene
expression analyses. Small non-coding RNAs can play
a dual role in tumorigenesis, acting as oncogenes
(e.g. miR-155 of miR-17-92 cluster family members)
or tumour suppressors (e.g. miR-15a and miR-16).
To date, there are three proposed mechanisms impli-
cating miRNA deregulation in cancer. These pro-
cesses involve chromosomal lesions at regions
encoding miRNAs, failure in their biosynthetic path-
way machinery, and epigenetic regulation. Among
the miRNAs that have been demonstrated to be up-regu-
lated in EC are miR-185, miR-106a, miR-181a, miR-
210, miR-423, miR-103, miR-107, miR-Let7c, miR-205,
miR-200c, miR-449, miR-429, miR-650, miR-183,
miR-572, miR-200a, miR-182, miR-622, miR-34a and
miR-205. In contrast, other miRNAs have been found
to be down-regulated, including miR-Let7e, miR-221,
miR-30c, miR-152, miR-193, miR-204, miR-99b, miR-
193b, miR-204, miR-99b, miR-193b, miR-411, miR-
133, miR-203, miR-10a, miR-31, miR-141, miR-155,
miR-200b and miR-487b.
5155
These miRNAs target
important genes in tumour development and progres-
sion, such as KCNMB1, IGFBP-6, ENPP2, TBL1X,
CNN1, MYH11, KLF2, TGFB1/1, MYL9, SNCAIP,
RAMP1, FOXO1, FOXC1 E2F3, MET and Rictor. In
one series, high levels of miR-205 expression were
associated with poor patient overall survival;
53
the
miRNA signature was different between EEC and ser-
ous carcinoma, and included miR-19a, miR-19b,
miR-30e-5p, miR-101, miR-452, miR-15a, miR-29c
and miR-382.
51
We have shown recently that the
miRNAs Lin28B and let-7b were involved in the reg-
ulation of the HMGA-2 gene, a factor that regulates
epithelial to mesenchymal transition, and which is
expressed frequently in MMMT and NEEC.
56
L O N G N O N - C O D I N G R N A S
Long non-coding RNAs (lncRNAs) are long (>200
nucleotide) transcripts from intergenic and intronic
regions of the human genome that lack protein-coding
capacity. They probably have important roles in
recruitment of histone-modifying complexes to chro-
matin and regulation of transcription and splicing.
Only a few lncRNA have been well characterized, but
expectations are that they will outnumber protein-
coding genes. Aberrant expression of these transcripts
has been documented in different types of cancer.
Some of them may play a role in EC. NC25 is a can-
didate tumour suppressor lncRNA, mapped to 6q13,
that has been shown to be expressed in EC, and to
exhibit mutations in almost half of EC samples that
have been tested.
57
Another lncRNA that may have
a role in EC is the PTEN pseudogene, PTENP1, which
can regulate PTENs tumour suppressor role by com-
petitive binding to common miRNAs.
58
Resistance to apoptosis, hypoxia and
radiation therapy in endometrial carcinoma
There is a great deal of evidence suggesting that
alteration of apoptosis is important in the develop-
ment and progression of EC (Figure 10). Several of
the molecular abnormalities that have been detected
in EC may be associated with apoptosis deregulation.
EEC show a high frequency of mutations in PTEN,
leading to constitutively active AKT which, in turn,
suppresses apoptosis triggered by various stimuli.
Moreover, the recent evidence that NF-jB activation
is frequent in endometrial carcinoma
59
may explain
the presence of apoptosis resistance by activation of
target genes such as FLIP and Bcl-xL. p53 altera-
tions, which are characteristic of NEEC, may also
occur in endometrioid tumours, particularly in those
neoplasms showing overlapping features between
types I and II tumours, and they may have an impact
on apoptosis at several different levels.
Also, members of the Bcl-2 family of genes are
abnormal in EC. In EC, divergent observations have
been reported with respect to Bcl-2 and Bcl-xL (Fig-
Death factors
Death receptors
Growth factors
PI3K
BCLxL
AP AF-1
CYT-C
Caspase 9
Caspase 3
Caspase 8
Adapter protein
APOPTOSIS
FLIP
BAX
PTEN
AKT
NFKB
Survivin
Figure 10. Apoptosis: intrinsic (mitochondrial) and extrinsic (death
receptor-initiated) pathways.
2012 Blackwell Publishing Ltd., Histopathology, 62, 111123.
118 X Matias-Guiu & J Prat
ure 10). Some authors have found up-regulated Bcl-
xL and Bcl-2 in EC compared to normal tissue, and
they have also been reported to be involved in devel-
opment of metastases. Many pathways can control
Bcl-2 expression, and typical EC molecular alterations
such as those involved in exacerbated PI3KAKT sig-
nalling could trigger Bcl-2 family members overex-
pression. However, other non-canonical molecular
events in EEC, such as those involving the NF-jB
pathway which plays an important role in tumori-
genesis, have been correlated in immunohistochemi-
cal studies with strong immunoreactivity for Bcl-xL.
The Bax family contains three former members: Bax,
Bak and Bok. All Bax family members contain Bcl-2
homology domains 13 and are therefore capable of
binding to anti-apoptotic Bcl-2 proteins. This is
thought to be the mechanism by which Bcl-2 anti-
apoptotic proteins inhibit cell death. Once activated,
Bax and Bak trigger permeabilization of the outer
mitochondrial membrane that, in turn, will promote
release of cytochrome C and other mitochondrial pro-
apoptotic factors to the cytosol, such as second mito-
chondria-derived activator of caspase (Smac)/DIA-
BLO, Omi/HtrA2 protease, endonuclease G and
apoptosis-inducing factor (AIF). Interestingly, Bax is
a target gene for mutations in EEC with MI, and may
have a role in resistance to apoptosis in these
tumours.
Cancer cells can evade the extrinsic apoptotic path-
way by several mechanisms. FLICE-like inhibitory
protein (FLIP), one of the most important regulators
of death receptor signalling (Figure 10), is a protein
that shares high homology with caspase-8 but lacks
proteolytic activity. Like caspase-8, it contains two
death-effector domains (DED) that allow it to interact
either with DED within Fas-associated death domain
protein (FADD) or caspase-8, thereby inhibiting
death-inducing signalling complex (DISC) assembly
and caspase-8 activation. Hence, FLIP represents a
potent inhibitor of cell death initiated by death recep-
tors. Moreover, FLIP overexpression seems to play a
key role in tumour evasion of the immune system.
Thus, FLIP-induced cell survival through inhibition of
the extrinsic apoptotic pathway appears to be critical
for the survival of many tumour cells. Direct evidence
for the role of FLIP in the resistance of endometrial
carcinoma cells to apoptosis induced by TNF-related
apoptosis-inducing ligand (TRAIL) is provided by
treatment with specic small interfering RNAs (siR-
NA) targeting FLIP.
60
Transfection of endometrial
carcinoma cell lines with FLIP siRNA results in a
marked decrease in cell viability after TRAIL exposi-
tion. This is accompanied by activation of both cas-
pase-8 and caspase-3, suggesting activation of the
extrinsic pathway. Moreover, in EEC, FLIP can be reg-
ulated transcriptionally by casein kinase-2 (CK2), a
Ser/Thr kinase implicated in the development and
progression of many neoplasias. These data point fur-
ther to CK2 as an important modulator of TRAIL sen-
sitivity. In fact, the CK2 beta regulatory subunit has
been found overexpressed in endometrial cancer com-
pared to normal tissue and is thought to regulate cell
proliferation and anchorage-independent cell growth.
Recent studies have shown that FLIP may be regulated
by a cellular complex, including CK2BRAFKSR1.
61,62
Interestingly, this regulation allows connection of apop-
tosis resistance with the RASRAFMEKERK signalling
pathway. The KSR1 (kinase suppressor of RAS 1) is
considered a scaffold protein that regulates the MAP
kinase pathway. KSR1 interacts with different kinases
of the RAFMEKERK signalling pathway to enhance
its activation and also modulates the apoptotic
response to death receptors. Recently, it has been
shown that the expression of KSR1 is increased in
EC, suggesting its possible role in endometrial carci-
nogenesis.
63
Tumour hypoxia is known to render tumours more
resistant to radiotherapy. By reacting with the radia-
tion-created broken ends of DNA, oxygen xes the
damage and thus enhances radiation-induced cell
death. This phenomenon, known as the oxygen
enhancement effect, could render oxygenated cells
three times more radiosensitive than hypoxic cells.
Under hypoxic conditions, the oxygen enhancement
effect is lost and cells become more radioresistant.
Although the absence of oxygen is the major factor
inducing radioresistance under hypoxic conditions,
there is increasing evidence that signalling pathways
activated under hypoxia may modulate cancer cell
radioresistance.
Some investigators have addressed the molecular
mechanisms involved in resistance to radiotherapy in
EC, including progesterone receptor (PR) expression
and a single specic polymorphism in the gene coding
for PR (so-called PROGINS allele). De-novo MLH-1
promoter methylation is found occasionally during EC
progression in patients receiving radiotherapy. By
comparing immunohistochemically tissue microarrays
from post-radiation recurrences of EC and a group of
primary EC, interesting information has been obtained
regarding the mechanisms of radioresistance. It has
been shown that post-radiation recurrences exhibited
increased expression of beta-catenin.
64
Recent work
has revealed hypoxia-induced beta-catenin nuclear
translocation in EC Ishikawa and HEC-1A cell lines.
Moreover, hypoxia induces an increase in TCF-4
2012 Blackwell Publishing Ltd., Histopathology, 62, 111123.
Endometrial carcinoma 119
reporter (Wnt reporter) activity in both endometrial
cell lines.
Hypoxia-inducible factor 1-alpha (HIF-1a) is
another candidate that could confer radioresistance
to EC cells. HIF-1 is the most important mediator of
hypoxia, as it controls the expression of more than
100 genes. It has been shown recently that HIF-1a
expression increases in post-radiation recurrences
compared to primary EC. HIF-1a controls the classical
NF-jB activation pathway and survival under
hypoxia through RelA (p65) nuclear accumulation.
Possibly, HIF-1a expression results in increased radio-
resistance.
65
Targeted therapies in endometrial
carcinoma
The PI3KAKT pathway is one of the most frequently
abnormal signalling pathways in EEC, often resulting
from mutations in the tumour suppressor gene PTEN
and activating mutations in PIK3CA. The importance
of the PI3KPTENAKT survival pathway in EC raises
the possibility that PI3K inhibitors may be used as
potential anticancer agents. In fact, a decrease of
AKT phosphorylation and increased apoptosis are
seen in mutated PTEN human endometrial cancer
cells in the presence of PI3K inhibitor. It has been
shown recently that EC tumours with PTEN muta-
tions have a high level of genetic instability and
defects in repair of DNA double-strand breaks by
homologous recombination, similar in some ways to
that seen for breast and ovarian cancers with altera-
tions in BRCA-1 and BRCA-2. For this reason, some
investigators have suggested using PARP inhibitors
in the treatment of patients with PTEN mutated EC.
66
Of particular interest among AKT targets is the
downstream effector mammalian target of rapamycin
(mTOR). AKT activates mTOR via direct phosphoryla-
tion of tuberous sclerosis 2 (TCS2) protein and by the
inhibition of 5-AMP-activated protein kinase (AMP-
PK), thereby activating Rheb (Ras homologue
enriched in brain) and mTORRaptor activity. Upon
activation, mTORRaptor phosphorylates S6K and
4EBP1, resulting in initiation of translation. The acti-
vation of mTORC1 downstream targets leads to pro-
tein synthesis, such as cell cycle regulating proteins,
vascular endothelial growth factor (VEGF) or c-Myc.
mTOR inhibitors (rapamycin and rapamycin deriva-
tives also called rapalogues) have been developed
recently as potential anticancer agents. Tumours
associated with PTEN inactivation, like EC, are partic-
ularly susceptible to the therapeutic effects of mTOR
inhibitors. Several mTOR inhibitors are available for
clinical trials: the prototype rapamycin and three ra-
pamycin derivatives, CCI-779 (temsirolimus),
RAD001 (everolimus) and AP23573 (ridaforolimus).
PTEN

mice are a good model for testing the sensitiv-


ity of EC to anticancer drugs, because they develop
complex atypical hyperplasia and endometrial carci-
noma.
The use of dual PI3KmTOR has been proposed as
a targeted therapy in EC.
67,68
The p110 subunits of
PI3K and mTOR share similar structures. Pharmaco-
logical inhibitors of p110 may also inhibit mTOR. It
has been shown that mTOR inhibitors often lead to
feedback activation of PI3K. Dual PI3K and mTOR
inhibitors may inactivate PI3K and mTOR, but also
reduce the feedback activation of PI3K caused
by mTOR inhibition, thus obtaining increased thera-
peutic effects. Considering the high frequency of
mutations in both PIK3CA and PTEN in EC, a dual
PI3KmTOR inhibitor, such as BEZ235, would be a
promising molecular-targeted therapy in endometrial
cancer.
Tyrosine kinase receptors are also good targets for
anticancer therapies. The epidermal growth factor
(EGF) receptor family and its growth factors are
known to play critical roles in cell growth and differ-
entiation. Increased expression of EGF-related protein
and epidermal growth factor receptor (EGFR) may
contribute to a drug-resistant phenotype. EGFR has
intrinsic tyrosine kinase activity which is activated
upon ligand binding. Inhibition of EGFR with mono-
clonal antibodies leads to growth arrest, and a similar
and potentially synergistic effect is anticipated with
inhibition of EGFR tyrosine kinase activity. Potential
agents are getinib, trastuzumab and lapatinib. Erloti-
nib, an EGF inhibitor, was associated with a response
rate of only 13% of EC patients. Sunitinib is an inhib-
itor of multiple tyrosine kinase receptors, including
c-kit, VEGFR, platelet-derived growth factor receptor
(PDGFR) and EGFR. It has also been shown recently
that sunitinib targets NF-jB.
Several multi-target kinase inhibitors targeting
FGFRs have been also proposed. These receptors
mediate signalling from their high-afnity ligands,
FGFs. FGF binding leads to FGFR dimerization, fol-
lowed by receptor autophosphorylation and activa-
tion of downstream signalling pathways. These
signalling pathways have been shown to contribute
to FGFR-mediated cell proliferation and migration.
Mutations in FGFR2 have been described in EC, pro-
viding a rationale for targeting FGFR2 to treat
patients with refractory tumours. Inhibition of FGFR2
kinase activity in EC cell lines bearing such FGFR2
mutations inhibits transformation and survival. Sev-
2012 Blackwell Publishing Ltd., Histopathology, 62, 111123.
120 X Matias-Guiu & J Prat
eral agents with activity against FGFRs are currently
in clinical trials.
Sorafenib is a potent receptor tyrosine kinase inhib-
itor with antiproliferative and anti-angiogenic activi-
ties that may result in clinical benet for a minority
of EC patients. There is recent evidence showing that
sorafenib sensitizes EC cells to TRAIL-induced apopto-
sis by down-regulating FLIP and Mcl-1.
69
Bevacizumab, a recombinant humanized immuno-
globulin monoclonal antibody to VEGF, has been used
in a small series of patients with recurrent EC, with
response in 20% and disease stabilization in 30%.
Oestrogen and progesterone are the most important
steroid hormones that modulate endometrial cell pro-
liferation and differentiation. Medroxiprogesterone
acetate has been studied in EC patients. Interestingly,
there is preclinical and clinical evidence that mTOR
inhibition may have a synergistic effect on hormonal
therapy.
Apoptosis may be also subjected to targeted ther-
apy. The recent evidence that NF-jB activation is fre-
quent in EC may explain the presence of apoptosis
resistance by activation of target genes such as FLIP
and Bcl-xL. Proteasome inhibitors are currently used
as chemotherapeutic drugs because of their ability to
trigger cell growth arrest or apoptosis on several
tumours.
70
In many different types of tumour cells,
bortezomib and other proteasome inhibitors cause cell
death by blocking NF-jB activity. Interestingly, block-
ade of NF-jB activity by tyrosine kinase inhibitor
sunitinib increases cell death in bortezomib-treated EC
cell lines.
71
There is increasing evidence that epigenetic altera-
tions contribute to cancer initiation and progression.
In contrast to genetic mutations, epigenetic changes
are reversible and are therefore an attractive target
for cancer therapy. Histone deacetylase inhibitors
(HDACi), such as vorinostat, are a relatively new
class of drugs that play important roles in epigenetic
or non-epigenetic regulation, inducing death, apopto-
sis and cell cycle arrest in cancer cells. Current inves-
tigations have suggested that HDACi have antitumour
activity against solid tumours.
Acknowledgements
This review was supported by grants FIS PI100922,
FIS PI11-01561, Fundaci on Mutua Madrile~ na
AP75732010, 2009SGR794, RTICC RD06/0020/
1034 and RD06/0020/0015; Fundaci on Asociaci on
Espa~ nola contra el Cancer, and programa de intensi-
caci on de la investigaci on, Instituto Carlos III, Depart-
ment of Health, Spain.
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Endometrial carcinoma 123
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