ARTICLE
Auteur(s) : Hüseyin
Engin, Esmen Baltali, Nilüfer Güler, Gülnur Güler, Gülten
Tekuzman, Aysegül Üner
Karaelmas University Faculty of medicine, Department of internal
medicine and medical oncology, 67600, Zonguldak, Turkey
PTEN is a multifunctional protein endowed with a phosphatase
activity capable of dephosphorylating not only proteins, at
tyrosine, serine or threonine residues, but also phospholipids of
the phosphatidylinositol pathway. Its protein phosphatase activity
allows it to inhibit the Ras/Mek/Erk cascade, as well as FAK, the
focal adhesion kinase, and thus to affect the interactions of cells
with the extracellular matrix which are important in the mechanism
of invasion. Its lipid phosphatase activity blocks the PI3K/Akt
pathway, provokes an arrest in G1 of the cell cycle and an
increased sensitivity to apoptosis [1]. Thus far, five studies of
PTEN protein expression in breast cancer reported reduced or absent
PTEN immunostaining in 33-50% of cases [2-6], with one study [3]
reporting that absent PTEN expression predicted inferior survival,
but only in univariate analysis.The cyclin D1 gene is amplified in
approximately 15-20% of breast carcinomas whilst overexpression of
it occurs in approximately 50% of the cases [7]. Several
publications have reported that 11q13 amplification in breast
cancer is associated with poor prognosis [8-10]. The prognostic
significance of cyclin D1 overexpression in human breast cancer has
yet to be resolved.P27/Kip1 is a universal cyclin dependent kinase
(CDK) inhibitor and arrests cells in G1 phase of the cell cycle
[11]. Several clinical studies have correlated absent or low p27
expression with poor prognosis in breast carcinomas [12-16].
However, these published series included only subgroups of cases
and other investigators failed to reproduce or only partially
confirmed the previously reported results. Particularly, low levels
of p27 were detected more frequently in lymph node negative breast
carcinomas compared with the lymph node positive ones in recent
published series [17].The aim of the present study was to determine
the interplay between PTEN, cyclin D1 and P27/Kip1 in breast
carcinoma samples and to evaluate the correlation of these
parameters with clinicopathologic characteristics.
Results
PTEN expression by Immunohistochemistry
Eighty-three cases were analyzed for PTEN protein expression
patterns. Reduced expression (1) was found in 26 (31.3%), equal
staining intensity compared to the corresponding normal tissue (2)
in 56 (67.5%) and no trace of staining (0) in 1 (1.2%) case.
Correlation of PTEN immunohistochemistry and
clinicopathological parameters
PTEN immunostaining status was compared with the following
clinicopathological parameters: menopausal status, size of primary
tumour, tumour grade, axillary lymph node (ALN) status, estrogen
receptor (ER) and progesterone receptor (PR) status, disease-free
survival (DFS), overall survival (OS), cyclin D1 and p27/Kip1
expression patterns. The only correlation found was between PTEN
and cyclin D1 expression (p = 0.05) (table 1( Table 1 )).
Table 1 Association between clinicopathological
parameters and PTEN
|
Variable
|
PTEN (reduced expression number)
|
PTEN (equal staining intensity number)
|
PTEN (no trace of staining)
|
p Value
|
|
Menopausal state
|
|
|
|
|
|
Premenopausal
|
11
|
31
|
1
|
|
|
Postmenopausal
|
15
|
25
|
0
|
0.1650
|
|
Tumour size
|
|
|
|
|
|
T1
|
10
|
17
|
0
|
|
|
T2
|
8
|
25
|
1
|
|
|
T3
|
8
|
12
|
0
|
|
|
T4
|
0
|
2
|
0
|
0.0806
|
|
Grade
|
|
|
|
|
|
Grade 1
|
7
|
15
|
N/A
|
|
|
Grade 2
|
7
|
26
|
|
|
|
Grade 3
|
12
|
14
|
|
0.1803
|
|
Lymph node involvement
|
|
|
|
|
|
Negative
|
12
|
30
|
0
|
|
|
Positive
|
15
|
26
|
1
|
0.1015
|
|
ER status
|
|
|
|
|
|
Negative
|
5
|
13
|
1
|
|
|
Positive
|
12
|
25
|
0
|
0.4415
|
|
PR status
|
|
|
|
|
|
Negative
|
10
|
14
|
1
|
|
|
Positive
|
12
|
24
|
0
|
0.3833
|
|
Cyclin D1
|
|
|
|
|
|
< 5%
|
23
|
38
|
N/A
|
|
|
≥ 5%
|
3
|
18
|
|
0.0500
|
|
P27/Kip1
|
|
|
|
|
|
≤ 50%
|
13
|
19
|
N/A
|
|
|
> 50%
|
14
|
37
|
|
0.1735
|
Cyclin D1 expression by immunohistochemistry
Eighty-three cases were analyzed for cyclin D1 expression patterns.
No trace of staining (0) was present in 38 (45.8%), < 5%
staining (1) in 23 (27.7%), between 5-50% (2) staining in 18
(21.7%), and > 50% staining (3) in 4 (4.8%) cases. There was
overexpression in 22 (26.5%) cases.
Correlation of cyclin D1 immunohistochemistry and
clinicopathological parameters
There were statistically significant correlations between cyclin D1
expression and tumour size (p = 0.027), and PTEN expression
patterns (p = 0.05) (table 2( Table
2 )).
Table 2 Association between clinicopathological
parameters and cyclin D1
|
Variable
|
Cyclin D1 (< 5%) Number
|
Cyclin D1 (≥ 5%) Number
|
p value
|
|
Menopausal status
|
|
|
|
|
Premenopausal
|
31
|
12
|
|
|
Postmenopausal
|
30
|
10
|
0.9802
|
|
Tumour size
|
|
|
|
|
T1
|
18
|
9
|
|
|
T2
|
27
|
7
|
|
|
T3
|
15
|
5
|
|
|
T4
|
1
|
1
|
0.0270
|
|
Grade
|
|
|
|
|
Grade 1
|
17
|
5
|
|
|
Grade 2
|
23
|
10
|
|
|
Grade 3
|
20
|
6
|
0.0961
|
|
Lymph node involvement
|
|
|
|
|
Negative
|
18
|
24
|
|
|
Positive
|
15
|
26
|
0.2948
|
|
ER status
|
|
|
|
|
Negative
|
9
|
9
|
|
|
Positive
|
17
|
20
|
0.1178
|
|
PR status
|
|
|
|
|
Negative
|
13
|
10
|
|
|
Positive
|
17
|
20
|
0.1348
|
|
PTEN
|
|
|
|
|
Reduced expression
|
23
|
3
|
|
|
Equal staining intensity
|
38
|
18
|
0.0500
|
|
P27/Kip1
|
|
|
|
|
≤ 50%
|
20
|
12
|
|
|
> 50%
|
40
|
11
|
0.1440
|
P27/Kip1 expression by immunohistochemistry
Eighty-four cases were analyzed for P27/Kip1 expression patterns.
No trace of staining (0) was present in 3 (3.6%), < 5%
staining (1) in 6 (7.1%), 6-50% staining (2) in 23 (27.4%), 51-89%
staining (3) in 26 (31.0%), and > 90% staining (4) in 26
(31.0%) cases. There was reduced expression of P27/Kip1 in 10.7%,
while overexpression of it was present in 89.3% of the cases.
Correlation of P27/Kip1 immunohistochemistry and
clinicopathological parameters
There was no correlation between P27/Kip1 expression and any of the
clinicopathological parameters tested (table 3( Table 3 )).
In univariate and multivariate survival analyses, there were no
correlation between PTEN, cyclin D1, P27/Kip1 expression patterns,
and DFS, OS.
Table 3 Association between clinicopathological
parameters and P27/Kip1
|
Variable
|
P27/Kip1 (≤ 50%) Number
|
P27/Kip1 (> 50%) Number
|
p value
|
|
Menopausal state
|
|
|
|
|
Premenopausal
|
18
|
25
|
|
|
Postmenopausal
|
14
|
27
|
0.0800
|
|
Tumour size
|
|
|
|
|
T1
|
10
|
18
|
|
|
T2
|
12
|
22
|
|
|
T3
|
9
|
11
|
|
|
T4
|
1
|
1
|
0.2680
|
|
Grade
|
|
|
|
|
Grade 1
|
10
|
12
|
|
|
Grade 2
|
13
|
21
|
|
|
Grade 3
|
8
|
18
|
0.2190
|
|
Lymph node involvement
|
|
|
|
|
Negative
|
10
|
32
|
|
|
Positive
|
22
|
20
|
0.2755
|
|
ER status
|
|
|
|
|
Negative
|
6
|
12
|
|
|
Positive
|
14
|
24
|
0.7901
|
|
PR status
|
|
|
|
|
Negative
|
11
|
13
|
|
|
Positive
|
11
|
26
|
0.4226
|
|
Cyclin D1
|
|
|
|
|
< 5%
|
20
|
40
|
|
|
≥ 5%
|
12
|
11
|
0.0964
|
|
PTEN
|
|
|
|
|
Reduced expression
|
13
|
14
|
|
|
Equal staining intensity
|
19
|
37
|
0.1015
|
Discussion
Five studies of PTEN protein expression in breast cancer reported
reduced or absent PTEN immunostaining in 33-50% of cases (2-6). In
this study, we have demonstrated reduced PTEN expression in 32.5%
of invasive breast cancers.
The correlation of loss of PTEN expression with outcome in
breast neoplasia remains controversial. Perren et al. [2] looked at
outcome variables including tumour grade, tumour size, ALN status,
and ER/PR status. They found association of PTEN loss with both ER
and PR loss. In a recent study by Bose et al. [5], clinical and
pathological parameters of the 13 cases of invasive carcinomas
with reduced PTEN expression were analyzed and compared to the
21 cases with no loss. The frequency of reduced expression was
highest in stage II and III cancers. Reduced expression was also
statistically significantly associated with aneuploidy. In our
study, the only statistically significant correlation was found
between PTEN and cyclin D1 expression pattern. In cases where PTEN
protein expression was reduced (23 cases, 88.5%) there was
reduced expression of cyclin D1. Even this finding was
contradictory to what could be physiologically expected. It could
be explained partially by the fact that what is found in vitro is
not always in accordance with what is expected in vivo.
Amplification of the cyclin D1 gene has been observed in 10-20%
of breast carcinomas [18]. However, the frequency of overexpression
of the gene product varies in breast carcinomas from 34 to 81%
[18-21]. In our study, overexpression for cyclin D1 was noted in
54.2% of cases.
Overexpression of cyclin D1 is seen in tumours that are positive
for expression of ER. Although ER-positive tumours generally have a
more favourable outcome, some studies have suggested that in
ER-negative tumours, overexpression of cyclin D1 is associated with
poor prognosis [22, 23].
Diest et al [23] correlated cyclin D1 overexpression with other
prognostic variables. Overexpression (59% of cases) of cyclin D1
was negatively correlated with histological grade, mean nuclear
area, mean nuclear volume, and mitotic activity and positively
correlated with ER expression (p = 0.0001). There was a strong
correlation between cyclin D1 overexpression and histological
subtype (p = 0.0001). There were no significant correlations with
ALN status, tumour size, or DNA ploidy.
Hwang et al. [24] evaluated expression of ER, cyclin D1,
c-erbB2, and p53 in 175 invasive breast cancers and correlated with
clinicopathological prognostic variables. In univariate survival
analysis, both cyclin D1 and ER overexpression correlated with
better OS (p = 0.020). There was a strong correlation between
cyclin D1 overexpression and tumour size (p = 0.031), low tumour
grade (p = 0.001) and ER positivity (p = 0.001). In this study, it
was concluded that overexpression of cyclin D1 is correlated with
poor prognosis in breast cancers, and with concomitant ER
expression it could serve as a prognostic factor for the
identification of good-risk patients.
In our study group, there were significant correlations between
cyclin D1 expression and tumour size (p = 0.027) as well as with
PTEN expression (p = 0.05). In the group where overexpression of
the cyclin D1 was observed, tumour sizes of the cases were as
follows: T1, 7 cases (31.8%), T2, 13 cases (59.0%), T3,
1 case (4.6 %), and T4, 1 case (4.6%).
Overexpression was mostly noted in small and early stage tumours.
There was no correlation between cyclin D1 and ER, PR status. In
survival analyses, cyclin D1 expression has not provided
significant univariate or multivariate prognostic value.
Mutations in the p27 gene are rare in human tumours and
regulation of this protein appears to occur primarily at the
posttranslational level by ubiquitin-mediated degradation [25,
26].
In breast cancer, low tissue expression of p27 has been shown to
be associated with other indicators of poor prognosis such as high
histologic grade and negative hormone receptor status [17, 27]. A
trend towards a correlation with metastatic lymph nodes was also
reported. Earlier studies have found p27 expression to be a
significant prognostic factor, independently of ALN status [28,
29].
Reed et al. [30] investigated the immunoreactivity of p27, p21,
cdk4, cyclin D1 and p53 in 77 node-negative breast carcinomas,
with long-term follow-up. Elevated levels of p27 and cyclin D1
correlated with positive hormone status (both ER and PR). They
found a significant correlation between p27 and cyclin D1 and
histological grade of the tumours, with extensive positive
immunostaining of p27 and cyclin D1 in well-differentiated
carcinomas. The only significant prognostic factor in their series
was the histological grade.
Nohara et al. [31] investigated the expression of p27 and cyclin
D1 immunohistochemically in a retrospective series of 216 breast
carcinomas. There was a positive association between p27 and cyclin
D1 and between p27 and ER. P27 was identified as an independent
prognostic factor in a multivariate Cox proportional hazard model
with a relative risk of death of disease of 4.1.
In our study, we found that p27/Kip1 expression was reduced in
10.7% of the cases (9 samples) and increased in 89.3% of the
cases (75 samples). We have not demonstrated any relation
between expression and tumour size. We have also not shown any
correlation between p27 and cyclin D1 expression. This could be
attributed to the small sample size and to the lower levels of
expression of p27 than expected in our study group. Also there was
no correlation between P27 expression and hormone receptor status
and lymph node status in contrast to previous reports. In
univariate and multivariate survival analyses, no effect of p27
expression could be demonstrated.
In conclusion, this is the first study in the literature
evaluating PTEN, cyclin D1, and P27/Kip1 expression patterns in the
same series of breast cancer samples. A larger number of samples
and longer follow-up are required to confirm the prognostic value
of these parameters in patients with breast cancer.
Material and methods
Patient group
Eighty-five cases operated with the diagnosis of breast carcinoma,
whose tumour tissue samples were adequate for immunohistochemical
evaluations, were enrolled in this study. All relevant clinical and
surgical information were retrieved from biopsy forms and files of
the patients protected in the archives of Hacettepe University
Adult Hospital, Ankara, Turkey. None of the patients had received
any preoperative therapy including neoadjuvant chemotherapy. All
patients were treated with modified radical mastectomy.
Postoperative locoregional radiotherapy was given in all lymph node
positive cases. FAC (fluorouracil, doxorubicin, cyclophosphamide)
was the standard adjuvant chemotherapy regimen and tamoxifen was
administered to patients with ER and/or PR positive tumours in the
adjuvant setting.
Immunohistochemistry
Immunohistochemical assays were performed on 5 μm sections
from paraffin-embedded tumour tissue samples. Slides were stained
using the biotin-strepdavidin immunoperoxidase method. The
antibodies used were as follows: PTEN (Novacastra, Newcastle UK),
cyclin D1 (Neomarkers, Fremont CA) and P27 (Novacastra, Newcastle
UK). Firstly, the sections were deparaffinized in xylene and
rehydrated through graded concentrations of ethanol to distilled
water. Deparaffinized sections were immersed in 80% methanol
containing 0.5% hydrogen peroxide for 10 minutes (min) to
block endogenous peroxidase activity. The deparaffinized slides
were pretreated before immunohistochemical stainings by boiling
them in 0.01 M tri-sodium citrate solution in a microwave oven
for 15 min at 700 W. After the microwave treatment, the
slides were allowed to cool down for 15 min, and incubated
with primary antibodies followed by avidin-biotin complex
conjugated to horseradish peroxidase was carried out, followed by
incubation with diaminobenzidene as a chromogen. Slides were rinsed
thoroughly with phosphate-buffered saline between all steps.
Finally, the sections were counterstained with haematoxylin.
Immunoscoring
For PTEN staining, the tumours were divided in three groups: the
group assigned (0) had no trace of staining; the group assigned (1)
had decreased staining intensity compared to the corresponding
normal tissue; and the group assigned (2) showed equal staining
intensity compared to the corresponding normal tissue.
The expression of cyclin D1 was scored according to the
percentage of cyclin D1 positive cancer cell nuclei. The tumours
were classified into four groups: the group assigned (0) had no
trace of staining; the group assigned (1) had < 5% staining; the
group assigned (2) had staining between 5% and 50%; and the group
assigned (3) had > 50% staining. Cases were defined as positive
for cyclin D1 immunostaining when over 5% of the cells were stained
in each section in accordance with the criteria described by Gillet
et al. [18].
The expression of p27 was scored according to the percentage of
p27 positive cancer cell nuclei. The tumours were classified in
five groups: the group assigned (0) had no trace of staining; the
group assigned (1) had ≤ 5% staining; the group assigned (2) had
6-50% staining; the group assigned (3) had 51-89% staining; and the
group assigned (4) had ≥ 90% staining. P27 was also scored as
having low (≤ 50% positive cells) or high (> 50%)
reactivity.
All staining assessments were undertaken by two of the authors
(A.Ü. and G.G.) independently and any cases with discrepant scores
were re-evaluated jointly.
Statistical analysis
Statistical analysis was conducted using the SPSS package program
(10.00 version). Correlation between PTEN, cyclin D1, P27/Kip1
protein expression patterns and clinicopathologic features was
estimated by the chi-square test when a cut-off value was used, and
a P value less than or equal to 0.05 was considered statistically
significant. When technically inadequate or inconclusive, cases
were excluded from the statistical assessment.
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