Download Immunohistochemical Assessment

EL-MINIA MED., BULL., VOL. 17, NO. 1, JAN., 2006
Abdelmonem & Abdelmeged
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IMMUNOCYTOCHEMICAL EXPRESSION OF CYCLIN D1 AND P21WAF1 IN
ENDOMETRIAL CARCINOMA.
By
Hanan Mohamed Abd ElMonem* and Ayman Nady Abd ElMeged**
Departmenst of *Pathology and **Obstetrics & Gynaecology,
El-Minia Faculty of Medicine
ABSTRACT:
For endometrial carcinoma patients, there is a need for improved identification
of high-risk groups that may benefit from postoperative adjuvant therapy. Aberrant
expression of several cell-cycle regulators has been reported in endometrial
carcinoma, correlations among some of these factors and their prognostic significance
have been systematically examined. Immunohistochemical expression of cyclin D1
and tumor-suppressor gene p21WAF1 in 32 endometrial carcinoma (EC), including 12
low-grade (grade I) and 20 high-grade (grade II or III) tumors was evaluated. Results
were compared with the expression of steroid receptor status, progesterone receptor
(PR). Positive staining for cyclin D1 and p21WAF1 was more frequent in higher grade
tumors and their expression were significantly frequent in advanced-stage tumors.
Ninety percent (18 of 20) of the high grade EC expressed cyclin D1 at a high level,
whereas only 42% (5 of 12) of the low grade EC did so (Chi2 = 8.7; P < 0.01). Sixtyfive percent (13 of 20) of the high grade EC expressed p21WAF1 at high levels, but
only 17% (2 of 12) of low grade EC did so (Chi2 = 7.0; P < 0.01). Coordinate high
level expression of p21WAF1 and cyclin D1 occurred in 65% (13 of 20) of high grade
EC but in only 17% (2 of 12) of the low grade EC (Chi2 = 7.0; P < 0.01). These
findings suggest that cyclin D1 and p21WAF1 are involved in activated cell growth of
endometrial carcinoma, and that positive staining for them could be a useful marker
for unfavorable patient prognosis.
KEY WORDS:
Endometrial carcinoma
Cyclin D1
P21WAF1.
(Jemal et al., 2003). Within the current
concept of multi-step progression of
normal cells to malignancy, recent
molecular work has identified several
gene alterations important for tumor
development. In summary, mutations
and amplifications of oncogenes K-ras
and HER2/neu, mutations or deletions
of tumor suppressor genes p53,
p21WAF1, p16, and pTEN/MMAC1 as
well as impaired DNA repair functions
through mutations of hMLH1, hMSH2,
and hMSH6 have been connected with
the development of endometrial carcinomas (Salvesen & Akslen 2002).
INTRODUCTION
Nearly 170,000 new cases of
endometrial carcinomas were estimated worldwide in 1997. However,
incidences throughout different regions
of the world vary considerably.
Compared to Africa and Asia having
the lowest rates of incidence, Western
Europe, USA and Canada are shown to
have the highest incidence worldwide
(Münstedt et al., 2004). Endometrial
cancer is the most common malignnancy of the female genital tract in
developed countries and is expected to
account for 6% of new cancer cases
among women in the United States
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Steroid hormones regulate
cellular proliferation and differenttiation by cell cycle phase-specific
actions (Musgrove & Sutherland,
1994). In contrast with the proliferative
effects of estrogen, progesterone acts
as the differentiating female sex
steroid. In this role it can either
stimulate or inhibit proliferation in a
cell type and tissue-specific manner
(Clarke & Sutherland, 1990). In breast
cancer cells, a widely used model for
studies of the effects of steroids on cell
proliferation, treatment with synthetic
progestins results in a biphasic change
in the rate of cell cycle progression,
consisting of an initial transient
acceleration through G1 phase and a
subsequent increase in the S phase
fraction, followed by cell cycle arrest
and growth inhibition accompanied by
a decrease in the S phase fraction
(Sutherland et al., 1988 and Musgrove
et al., 1991). Data from both breast
cancer cells in tissue culture and in
vivo studies of the uterus and
mammary gland demonstrate that
sensitivity to both stimulation and
inhibition is present only during G1
phase (Sutherland et al., 1988, Clarke
& Sutherland, 1990, and Musgrove et
al., 1991). The most extensively
studied biologic markers in endometrial carcinoma are estrogen and
progesterone receptors. It has been
shown that high levels of estrogen and
progesterone receptors directly correlate with better tumor differentiation,
less myometrial invasion, and a lower
incidence of nodal metastases and that
they independently predict better
survival (Zaino et al., 1983, and
Creasman, 1993). Estrogen exposure,
when in excess and in the absence of
progesterone influence, causes continued stimulation of the endometrium
and is strongly associated with
increased endometrial carcinoma risk
(Salvesen et al., 1998). Progesterone
exposure attenuates endometrial cancer
risk, and this is attributed to interruption of continued estrogenic stimulation of the endometrium (Lentz, 1998
and Marsden & Hacker, 2001).
Recent studies have revealed
that cell growth is controlled by
interactions of cell cycle-related molecules such as cyclins, cyclin-dependent
kinases (cdks), and tumor-suppressor
gene products. Cyclins D1, E, A, and
B1 are expressed in a cell-cycle–
specific manner, and they form complexes with their respective cdk’s. These
complexes phosphorylate substrates
such as retinoblastoma gene products
(pRB), leading to cell growth (Sherr,
1994). Cell proliferation allows orderly
progression through the cell cycle,
which is governed by a number of
proteins including cyclins and cyclin
dependent kinases (Hunter & Pines
1994 and Cordon-Cardo, 1995). The
cyclins belong to a superfamily of
genes whose products complex with
various
cyclin-dependent
kinases
(cdks) to regulate transitions through
key checkpoints of the cell cycle
(Bartkova et al., 1994). Abnormalities
of several cyclins have been reported
in different tumor types, implicating, in
particular, cyclin A, cyclin E and
cyclin D (Motokura & Arnold, 1993
and Bartkova et al., 1994). Cyclin D1
is a G1 cyclin that regulates the
transition from G1 to S phase since its
peak level and maximum activity are
reached during the G1 phase of the cell
cycle (Handa et al., 1999). The
mechanisms likely to activate the oncogenic properties of the cyclins include
chromosomal translocations, gene
amplification and aberrant protein
overexpression (Motokura & Arnold,
1993 and Gillett et al., 1994).
Over the past few years, it has
been shown that p53 has a central role
in the regulation of cell-cycle
progression by the transcriptional
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activation of genes such as p21WAF1,
followed by inhibition of cyclindependent kinases (Jacks & Weinberg
1996 and Kinzler & Vogelstein 1996).
Hence, p21WAF1 (also known as WAF1,
CIP1, and SDI1) seems to be a critical
downstream effector in the p53specific pathway of growth control,
and its inactivation could potentially
lead to tumor progression (El-Deiry et
al., 1993 and Gartel et al., 1996). It
has also been shown that p21WAF1 can
be downregulated in tumors without
p53 alterations, which indicates that
additional mechanisms are involved in
p21WAF1 inactivation (Bukholm et al.,
1997). Until recently, members of the
Cip/Kip family were considered
universal inhibitors of CDK activity.
The demonstration that both p21WAF1
and p27Kip1 are components of active
cyclin·CDK complexes (Zhang et al.,
1994 and Blain et al., 1997) and that
p21WAF1 can promote the assembly of
cyclin D·CDK4 complexes in vitro
(LaBaer et al., 1997) has stimulated the
re-evaluation of this hypothesis.
 Personal history of breast or colon
cancer.
 Family history of breast, ovarian,
or colon cancer.
 PCOS and granulosa cell tumors
of the ovary.
PATIENTS & METHODS:
Study Design:
This is an analytic descriptive
and prospective study. Thirty two
endometrial carcinoma patients were
surgically treated by extrafascial
hysterectomy and bilateral salpingoophrectomy in the department of
Obstetrics & Gynaecology, Minia
University.
Surgical Approach:
All patients had a mechanical
bowel preparation before surgery. The
usual anti-thrombotic measures undertaken and prophylactic antibiotics were
given on induction of anesthesia.
Women were subjected to surgical
staging using the criteria of (FIGO
1989). All the malignant cases were
subjected to extrafascial hysterectomy
and bilateral salpingoophrectomy .
 Specimens were opened and tumor
size, myometrial invasion, and cervical
extension were assessed, then the
specimens were sent for frozen section
examination.
 Peritoneal cytology, pelvic lymph
node sampling and excision or biopsy
of any extra-uterine lesions suggestive
of metastasis cancer was done.
Diagnostic Techniques:
 To confirm diagnosis of endometrial carcinoma, all patients with
risk factors were subjected to endometrial biopsy, vaginal ultrasonography, hystroscopy and dilatation and
curettage.
 Twelve of EC were low grade
(grade 1), and twenty were high grade
(grade 2 and 3).
 Endometrial carcinoma patients
were subjected to the following
preoperative investigations: CBC,
serum creatinine levels, blood glucose
level, urine analysis, liver function
tests, ECG, chest radiograph.
 Proctoscopy, barium enema, CT
scan was reserved for cases in which
advanced disease was suspected and
when a precise diagnosis was unclear.
Inclusion Criteria:
 Women who presents with vaginal
bleeding and is noted to have disease
confined to the uterus or abnormal
vaginal discharge, pelvic heaviness,
crampiness, or pain.
 Postmenopausal patients who are
obese and nulliparous.
 History of unopposed estrogen
therapy, early menarche or late
menopause, chronic anovulation.
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 Paraaortic lymph node samples
were done in the following conditions:
Tumor histology proved to be clear cell
carcinoma, serous, squamous or grade
III endometrioid
carcinoma,
if
myomertrial invasion more than half
thickness, isthmus cervix extension,
tumor size > 2 cm or presence of extra
uterine lesion. Twenty of EC were
stage I, 5 cases were stage II, 5 cases
were stage III, and 2 cases were stage
IV. The mean age of patients was ±52
years.
used as positive internal controls for
both cyclin D1 and p21WAF1 antibodies
and breast cancer was used as positive
control for (PR). Negative controls
were analyzed on adjacent sections
incubated without antibody. After a
PBS rinse, the sections were treated
with biotinylated goat antimouse
antibody for 15 min. The sections were
washed with PBS three times and
incubated with an avidin-biotinylated
horseradish
peroxidase
macromolecular complex for 10 min
according to the manufacturer’s
instructions for the LASB kit.
Visualization of peroxidase was carried
out by incubating the sections with
diaminobenzidine for 10 min. The
sections were counterstained with
hematoxylin, dehydrated in a series of
ethanol solutions, and cleared with
xylene, and coverslips were placed
over mounting medium for evaluation
by light microscopy.
Immunohistochemical Assessment:
Immunostaining for cyclin D1
and p21WAF1 was performed on 5 µm
sections of formalin-fixed, paraffinembedded endometrial specimens
using DAKO LSAB kits (Dako,
Cytomation,
Carpinteria,
CA).
Expression of PR was also examined
by immunohistochemical analysis.
Tissue sections were incubated at 60°C
for 1 h, deparaffinized in xylene, and
hydrated in a graded series of ethanol
solutions. After a rinse in PBS (137
mM NaCl, 2.7 mM KCl, 1 mM
KH2PO4, and 10 mM Na2HPO4; pH
7.4), endogenous peroxidase activity
was quenched by incubating the
sections for 15 min with 0.3% H2O2 in
absolute methanol. Then, after a 10min rehydration in PBS, the sections
were heated in a microwave oven for 3
min in 10 mM citrate buffer for antigen
retrieval.
After incubation with
blocking serum (4% normal horse
serum) for 30 min at room
temperature, the sections were
incubated overnight at 4°C with
monoclonal antibodies against human
cyclin D1 (mouse monoclonal DCS-6,
DAKO), p21WAF1 (Pharmingen, San
Diego, CA) and progesterone receptor
(PR) (Human PR-8, clone 16,
Novocastra). Each antibody was tested
in serial dilutions to achieve maximum
sensitivity and specificity. Infiltrating
lymphocytes and stromal cells were
For each case a total of 1000
cells were assessed in three to four
different fields at x400 magnitudes.
Scores for the expression of cyclin D1,
p21WAF1 and PR were assigned semiquantitatively according to the percentage of cells stained (<25%, score 1;
25–75%, score 2; and >75%, score 3)
and the intensity of staining (weak,
score 1; moderate, score 2; and strong,
score 3). The two scores were then
multiplied. When <25% of the cells
were stained or the intensity of the
stain was weak, then the product of the
two scores was 3, and expression was
categorized as low. When at least 25%
of the cells were stained, and the
intensity of the stain was moderate or
strong, then the product of the two
scores was at least 4, and expression
was categorized as high.
Statistical Analysis:
Chi-Square (Chi2) test was
used to evaluate the association
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between two categorical variables. P <
0.05 was considered to be statistically
significant.
high expression of cyclin D1 and
p21WAF1 was present in 65% (13 of 20)
of high grade EC but in only 17% (2 of
12) of low grade EC (Chi2 = 8.5; P <
0.01; Table 2). In the present study,
staging was done according to the
criteria of FIGO (1989). On comparing
cyclin DI and p21WAF1 expression with
different lesions according to surgical
staging, there was a significant
difference with tendency to up-regulate
with advanced surgical staging (p <
0.05) (Table 3 & 4) .
RESULTS:
Microscopic evaluation of the
immunohistochemical staining of the
endome-trial specimens resulted in the
categorization of their expression of
cyclin D1 and p21WAF1 as low or high
(Table
1).
Examples
of
the
immunostaining show that expression
of cyclin D1, p21WAF1 and PR was
confined to the cell nuclei.
To assess the functional
consequence of coordinate high
expression of cyclin D1 and p21WAF1,
the expression level of PR was
determined by immunohistochemical
analysis. Positive PR expression was
found to be 59.4% (19 of 32) total EC
tumors (Figure 4). Of (12 low grade
and 20 high grade), 15 showed
coordinate high expression of cyclin
D1 and p21WAF1. Low level expression
of PR was present in 27% (4 of 15) of
cases with coordinate expression of
cyclin D1 and p21WAF1. In contrast,
88% (15 of 17) of cases showed highlevel of PR expression in cases without
coordinate expression (Chi2 = 9.6; P <
0.01; Table 5).
Expression of cyclin D1 and
p21WAF1 was high in the majority of
the high-grade EC specimens, but not
present in the majority of low grade
EC. P21WAF1 was expressed at high
levels in 65% (13 of 20) of the high
grade EC (Figures 1 and 2), but in only
17% (2 of 12) of the low grade EC
(Chi2 = 7.0; P < 0.01). So p21WAF1
was expressed in (46.9%) 15 out of 32
cases. Cyclin D1 was expressed at high
levels in 90% (18 of 20) of high grade
EC (Figure 3), but in only 42% (5 of
12) of low-grade EC (Chi2 = 8.7; P <
0.01). This includes expression of
cyclin D1 in (72.9%) 23 out of the total
EC cases. Furthermore, coordinate
Table 1: Expression of cyclin D1 and p21WAF1 in malignant endometrial tissue.
Expression of cyclin D1
Histological feature
Total no.
Lowa
Highb
32
9 (28%)
23 (72%)
EC
12
7 (58%)
5 (42%)
Low grade (I)
20
2 (10%)
18 (90%)
High grade (II& III)
a
( ) Stain weak in intensity, or <25% of cells stained.
(b) Stain moderate or strong intensity, and 25% of cells stained.
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Expression p21WAF1
Lowa
Highb
17 (53%)
10 (83%)
7 (35%)
15 (47%)
2 (17%)
13 (65%)
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Table 2: Coordinate high expression of cyclin D1 and p21WAF1 in low and high-grade
EC.
Histological
feature
Tota
l no.
EC
Low grade (I)
32
12
High
expression of
cyclin D1
23
5
High grade
(II&III)
20
18
High expression
of p21WAF1
Coordinate high expression
cyclin D1 and p21WAF1
15
2
15 (47%)
2 (17%)
14
14 (70%)
Table3: Cyclin D1 expression in different stages of endometrial carcinoma.
Expression of cyclin D1
Low
Stage I
n = 20
13 (65%)
StageII
n=5
2 (40%)
Stage III
n=5
1 (20%)
Stage IV
n=2
-
High
7 (35%)
3 (60%)
4 (80%)
2 (100%)
Chi2 = 15.25
P value < 0.05.
Table 4: P21waf1 expression in different stages of endometrial carcinoma.
Expression p21WAF1
Stage II
n=5
3 (60%)
Stage III
n=5
2 (40%)
Stage IV
n=5
Low
Stage I
n = 20
12 (60%)
High
8 (40%)
2 (40%)
3 (60%)
2 (100%)
Chi2 = 12.50
P value < 0.05.
Table 5: Correlation of PR expression with coordinate expression of cyclin D1 and
p21WAF1 in EC.
Total no. of
EC
PR
expression
32
(19/32)
59.4%
PR expression in tumors
with coordinate
expression
(4/15)
27%
P value < 0.01.
27
PR expression in tumors
without coordinate
expression
(15/17)
88%
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Figure 1: Immunohistochemical nuclear staining for p21WAF1 was strong in
selected samples of high grade endometrial carcinoma. X400.
Figure 2: Immunohistochemical staining for p21WAF1 was focally nuclear in
selected samples of endometrial carcinoma. Staining for p21WAF1 was strong in a
majority of samples of high-grade EC. X100.
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Figure 3: Immunohistochemical staining for Cyclin D1 was nuclear in a
majority of samples of high grade endometrial carcinoma EEC. X400.
Figure 4: Immunohistochemical nuclear staining for PR in low grade
endometrial carcinoma. X100.
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1991) and head and neck squamous
cell carcinoma (Williams et al., 1993).
The mechanisms of cyclin D1
dysregulation in endometrial neoplasia
are not well defined, but it is likely that
the dysregulation contributes to an
increase in the proportion of cells in
transition from G1 to S phase. Cyclin
Dl overexpression may be one of
several mechanisms involved in
endometrial
neoplasia,
and
proliferative endometrial glands and
stroma, even when actively mitotic, do
not overexpress cyclin D1. Cyclin D1
dysregulation may have a role in
endometrial carcinogenesis, about 40%
of endometrial carcinomas overexpress
cyclin D (Nikaido et al., 1996).
DISCUSSION:
Cyclin D1 (PRAD-1, CCND-1)
is located on chromosome 11q13 and
exhibits many characteristics of
cellular oncogenes (Sher, 1994, and
Hirama & Koeffler, 1995). Cyclin D1
forms a complex with cdk4 in the G1
phase of the cell cycle; this complex
formation is critical in the initiation of
the cell cycle (Sherr, 1994). Nikaido et
al., 1996 detected cyclin D1
overexpression in 40% (30/74) of cases
with endometrial adenocarcinoma
compared with 72.9% reported in our
series. Also in our study expression of
cyclin D1 was high in the majority of
the high-grade EC specimens, in 90%
(18 of 20) of high grade EC, but in
only 42% (5 of 12) of low-grade EC.
Positive staining for cyclin D1 and
cdk4 was observed more frequently in
the tumors of advanced stages and
those of higher histological grade. In
addition, the expression of cyclin D1
and cdk4 were significantly correlated
with the proliferative index of Ki-67 in
endometrial carcinomas (Sherr &
Roberts 1995). These findings suggest
that accumulation of cyclin D1 may
also contribute to active growth
potentials in endometrial carcinomas.
Overexpression of cyclin D1 may be
associated
with
actual
gene
amplification
or
transcriptional
dysregulation in cancers (Ruhul et al.,
2002). Cyclin D1 and cyclin-dependent
kinases are required for completion of
the G1/S transition in normal
mammalian cells (Lukas et al., 1994
and Hirama & Koeffler 1995).
Overexpression of cyclin DI is
associated with mantle cell lymphoma
(Rosenberg et al., 1991 and Swerdlow
et al., 1995), squamous cell carcinoma
of the uterine cervix (Nichols et al.,
1996), ovarian carcinoma (Foulkes et
al., 1993), breast cancer (Karlseder et
al., 1994), transitional cell carcinoma
of the urinary bladder (Proctor et al.,
Cyclins, cyclin-dependent kinases,
and tumor suppressor gene products
interact and regulate the normal cell
cycle (Sher, 1994). P21WAF1 has been
shown to be involved in reversible and
irreversible growth arrest, apoptosis,
terminal differentiation, and possibly
cell death due to necrosis (Sheikh et
al., 1995 and Mobley et al., 1998).
Defects in the mechanisms controlling
the cell cycle are crucial in cell
transformation
and/or
tumor
WAF1
progression. P21
is an inhibitor of
cyclin-dependent kinases, induced by
p53-dependent and p53-independent
pathways, which can block progression
through the cell cycle (Ioachim et al.,
2003). In our series p21WAF1 was
expressed at high levels in 65% (13 of
20) of the high grade EC, but in only
17% (2 of 12) of the low grade EC
(Chi2 = 7.0; P < 0.01). So p21WAF1 was
expressed in (46.9%) 15 out of 32
cases. Interestingly positive staining
for
p21WAF1
was
significantly
correlated with higher histological
grade and Ki-67 expression, expression
of p21WAF1 could be a poor prognostic
factor. These findings indicate that cell
cycle progression was not suppressed
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in the tumor cells associated with
accumulation of p21WAF1 (Ito et al.,
1997). Salvesen et al., (1999) found a
significantly decreased survival among
patients with low p21WAF1 expression
in univariate analysis. Nuclear p21WAF1
expression was statistically higher in
the group of carcinomas compared
with normal proliferative and secretory
endometrium.
In addition, this
expression was higher in hyperplastic
lesions
compared with
normal
proliferative
and
secretory
endometrium. These data indicate that
the expression of p21WAF1 protein
seems to be an early event in
endometrial carcinogenesis and is
strongly associated with other cell
cycle related proteins (Ioachim et al.,
2003). Evidence that p21WAF1 and p27
proteins function as regulators of
cyclin D1 nuclear accumulation based
largely on the ability of p21WAF1 and
p27Kip1 to promote nuclear localization of cyclin D1·CDK4 complexes
in transient transfection experiments
(Diehl & Sherr 1997 and LaBaer et al.,
1997). It was proposed that Waf/Kip
proteins are regulators of cyclin D1
nuclear import (Polyak et al., 1994 and
Goubin & Ducommun 1995). However
three pieces of evidence demonstrate
that neither p21WAF1 nor p27Kip1 are
strictly required for cyclin D1 nuclear
import. First, although inefficient, low
levels of cyclin D1 can still enter the
nucleus of p21/p27. Second, nuclear
localization of cyclin D1 in p21/p27
can be completely restored by inhibition of the nuclear exportin CRM1
with leptomycin B. Third, cyclin D1T286A, a cyclin D1 mutant that is
refractory to CRM1-dependent nuclear
export, is exclusively nuclear in the
absence of both p21WAF1 and p27Kip1.
Although neither p21WAF1 nor p27Kip1
is strictly required for cyclin D1
nuclear import, the possibility that they
may also facilitate cyclin D1 nuclear
import under certain conditions cannot
be eliminated. By increasing nuclear
import and inhibiting nuclear export of
cyclin D1, Cip/Kip proteins would
ensure
the
efficient
nuclear
accumulation of cyclin D1 during G1phase (Alt et al., 2002).
Our studies have now identified
positive PR expression in 59.4% (19 of
32) total EC tumors. Of (12 low grade
and 20 high grade), 15 showed
coordinate high expression of cyclin
D1 and p21WAF1. Low level expression
of PR was present in 27% (4 of 15) of
cases with coordinate expression,
whereas high PR expression was a
feature of low grade tumors. High
expression of PR was significantly
associated with tumors of low grade,
which are associated with good
prognosis (Salvesen et al., 1999). This
supports previous findings showed that
reduced PR expression is associated
with
poorer
prognosis
tumor
phenotypes (Fukuda et al., 1998 and
Mansfield et al., 2001). A statistically
significant positive relationship of
p21WAF1 expression with progesterone
receptor
status
and
the
two
proliferative associated indices Ki-67
and PCNA was observed by (Ioachim
et al., 2003). Pathways by which
progesterone limit endometrial cancer
cell growth and metastatic potential in
a highly malignant cell line that do not
express ER. In these investigations,
the cell cycle was inhibited in late G1
by induction of p21 and p27 cells
could no longer invade through a
matrigel chamber cells underwent
conversion to a more differentiated,
secretory phenotype replicative sensecence was induced; and apoptosis
ensued when growth factors were
removed from the medium. These
effects were dependent on the
expression of PR (Dai et al., 2002).
Therefore, elevated expression
of cyclin D1 is a characteristic feature
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of high grade endometrial carcinomas
associated with p21WAF1 expression.
Thus the topologic correlation between
the expression of cyclin D1 and
p21WAF1 in endometrial carcinomas
might represent the possible interactions of these molecules.
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8. Dai D, Wolf DM, Litman ES,
White MJ, and Leslie
KK.:
Progesterone inhibits human endometrial cancer cell growth and invasiveness. Down-regulation of cellular
adhesion molecules through progesterone B receptors. Cancer Research
2002; 62: 881-886.
9. Diehl JA, and Sherr CJ.: A
dominant-negative cyclin D1 mutant
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phosphorylation by CDK-activating
kinase.Mol.Cell.Biol.1997;17:7362-7374
10. El-Deiry WS, Tokino T, and
Velculescu VE.: WAF1, a potential
mediator of p53 tumor suppression.
Cell 1993; 75: 817-825.
11. Foulkes WD, Campbell IG,
Stamp GW, and Trowsdale J.: Loss of
Improvements in prognosis for
majority of patients with endometrial
carcinoma will not be apparent even
with data form randomized studies
because their prognosis is so good.
However, management will be improved for them, as few of them need
adjuvant therapy and those who relapse
can be salvaged successfully with
radiotherapy. These data should allow
us to be in a position to refine rather
than define treatment protocols.
Immunohistochemical expression of
cyclin D1 and p21WAF1 in endometrial
carcinoma could allow us to predict
those cases of poor prognosis and be
helpful in selection of cases for
adjuvant therapy and decreasing
recurrence after surgical treatment.
Further
molecular
studies
are
warranted to investigate the role of
cyclin D1 and p21 WAF1 expression in
endometrial carcinoma patients and
their correlation with adjuvant radiotherapy. More aggressive treatment
strategies would be developed for high
risk groups with high expression of
cyclin D1 and p21WAFI and there’s a
very strong argument for entering these
patients into randomized trials,
comparing for instance, whole
abdominal
radiotherapy
with
cytotoxics. For the more distant future,
disease prevention is clearly the aim,
but in short term, encouragement of
surgery and less radiotherapy with the
aid of cyclin D1 and p21WAF1
expression.
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‫تعبير الصبغه المناعيه الهيستوكيمائيه لسيكلين د‪ 1‬وب‪11‬‬
‫فى سرطان الرحم‬
‫حنان محمد عبد المنعم* و أيمن نادى عبد المجيد**‬
‫أقسام *الياثولوجيا و **أمراض النساء والتوليد‬
‫كلية طب المنيا‬
‫يحتاج مرضى سرطان الرحم لتحسين طرق التعرف إلى المجموعات المعرضه لططهر‬
‫سرطان الرحم لإلستفاده من العالج الالزم لما بعد العملي ‪ .‬وجد أن تعبير منظم دورة الطليه له‬
‫عالقههب بتطههور سههرطان الههرحم‪ .‬تههم ت يههيم تعبيههر سههييلين دب ‪ 12‬فههى ‪ 21‬عين ه مههن حهها ت‬
‫سهرطان الهرحم و تلههم ‪ 21‬حاله مهن منطفضههى الدرجه ب ‪ 12‬حاله مههن مرتفعهى الدرجه ‪ .‬تههم‬
‫م ارنب النتائج بتعبير حالب المست ب الهرمونى الستيرويدى (مست ب بروجيستيرون)‪.‬‬
‫إن إيجابيب صبغب سييلين د‪2‬ب ‪ 12‬أيثر لده فى مرتفعى درجب الورم حيث أن ‪/ 21( % 02‬‬
‫‪ )12‬من مرتفعى درجب سرطان الرحم و ‪ ) 21 / 5( % 21‬من منطفضى درجب سرطان الرحم‬
‫تظهههر سههييلين د‪ 2‬بنسههب عالي ه ‪ .‬بالنسههب لتعبيههر ‪ 12‬ف ه ن ‪ )12 / 22 ( % 55‬مههن مرتفعههى‬
‫درجب سرطان الرحم و ‪ % 21‬ف ط ( ‪ ) 21/ 1‬من منطفضى درجب سرطان الرحم تظهر ‪12‬‬
‫بنسب عالي ‪.‬‬
‫هذه النتائج ت ترح أن سييلين د‪2‬و ‪ 12‬يلتريوا فى تنليط نمو الطلي فى سرطان الهرحم و أن‬
‫إيجابيب الصبغ لهم يمين إستطدام يدلي على سوء تطور حالب المرضى‪.‬‬
‫‪35‬‬