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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 27  |  Issue : 1  |  Page : 1-9

Immunohistochemical expression of topoisomerase II a and tissue inhibitor of metalloproteinases 1 in locally advanced breast carcinoma


1 Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El-kom, Egypt
2 Department of Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
3 Department of Oncology, National Cancer Institute, Cairo University, Cairo, Egypt

Date of Submission18-Aug-2013
Date of Acceptance08-Oct-2013
Date of Web Publication20-May-2014

Correspondence Address:
Shereen F Mahmoud
Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El-kom, Berkt El-Sabea Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.132294

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  Abstract 

Objectives
To evaluate immunohistochemical expression of topoisomerase II a (TOP2α) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in an attempt to identify their prognostic roles in locally advanced breast cancer (LABC).
Background
LABC is a heterogeneous clinical entity that remains a clinical challenge. Efforts are still needed to identify new markers in an attempt to predict response to therapy and prognosis.
Patients and methods
This study included 84 pretreatment needle core biopsies of LABC cases subjected to TOP2α and TIMP-1 immunohistochemical staining and the expression was correlated with some prognostic clinicopathlogical parameters of the patients studied.
Results
Fifty-seven of 84 cases (67.9%) showed positive TOP2͍ expression, with the proportion of TOP2α immunopositive cells (%score) ranging from 0 to 95%, mean ± SD of 27.84 ± 26.16%, and the median was 25%. Positive TOP2α expression was significantly associated with the presence of necrosis (P = 0.03). There was also a near-significant association between positive TOP2α expression and high mitotic count (P = 0.08). Forty-eight of 84 cases (57.1%) showed positive TIMP-1 expression with proportion of TIMP-1 immunopositive cells (%score) ranged from 0 to 95%, mean ± SD of 35.59 ± 32.93%, and the median was 30%. Positive TIMP-1 expression was significantly associated with a low apoptotic count (P = 0.03).
Conclusion
TOP2α-positive expression in diagnostic samples of LABC patients is associated with poor prognostic features such as the presence of necrosis, whereas TIMP-1 is associated with a low apoptotic count.

Keywords: Invasive duct carcinoma, tissue inhibitor of metalloproteinases 1, topoisomerase II ͍


How to cite this article:
El Rebey HS, Aiad HA, Asaad NY, Abd El-Wahed MM, Abulkheir IL, Abulkasem FM, Mahmoud SF. Immunohistochemical expression of topoisomerase II a and tissue inhibitor of metalloproteinases 1 in locally advanced breast carcinoma. Menoufia Med J 2014;27:1-9

How to cite this URL:
El Rebey HS, Aiad HA, Asaad NY, Abd El-Wahed MM, Abulkheir IL, Abulkasem FM, Mahmoud SF. Immunohistochemical expression of topoisomerase II a and tissue inhibitor of metalloproteinases 1 in locally advanced breast carcinoma. Menoufia Med J [serial online] 2014 [cited 2020 Feb 17];27:1-9. Available from: http://www.mmj.eg.net/text.asp?2014/27/1/1/132294


  Introduction Top


Breast cancer is the most common cause of cancer death among women worldwide [1]. In Egypt, breast cancer is the most common cancer among women, representing 17.5% of total cancer cases received at the National Cancer Institute from 2003 to 2004 [2].

Locally advanced breast cancer (LABC) is a heterogeneous clinical entity that includes patients with large (>5 cm) primary breast tumors (T3), with skin and chest wall involvement (T4), or inflammatory carcinoma and/or extensive clinical lymph node involvement, as defined by the N2 and N3 categories from the American Joint Committee on Cancer TNM classification system [3],[4],[5].

The incidence of LABC in Egypt represented 33.24% according to the Gharbiah Population-based Cancer Registry [6]. In other developing Asian countries, it accounts for 50% of all breast cancers according to Giordano [7] and Dey et al. [8]. Studies carried out in developed countries showed that LABC represents 10-15% of all new primary breast cancer diagnoses [9]. Furthermore, Akhtar et al. [10] reported that stage II was predominant in western countries. This indicates the aggressive nature of the disease in Egypt. Thus, it is very critical to identify new markers in an attempt to predict response to therapy and patient outcome [11].

Topoisomerase II a (TOP2α) and tissue inhibitor of metalloproteinases 1 (TIMP-1) are newly discovered prognostic markers in LABC. TOP2α is a key enzyme in DNA metabolism, playing a central role in DNA replication. It first acts by generating and then resealing double-stranded DNA breaks, which are necessary for segregation of chromosomes at the end of mitosis. TOP2α reduces DNA twisting and supercoiling, allowing selected regions of DNA to untangle and thus engage in transcription, replication, or repair processes [12].

TIMP-1 is an endogenous inhibitor of matrix metalloproteinase activity, the proteolytic enzymes responsible for degradation of extracellular matrix that is required for cancer dissemination. In addition, TIMP-1 has been shown to be involved in cell proliferation, angiogenesis, and apoptosis [13].

Conflicting data on the prognostic significance of TOP2α and TIMP-1 have been reported. Some studies found an important association of TOP2α expression and worse prognosis [14]. By contrast, some other studies reported an association of TOP2α expression with good prognosis [12], whereas in several other reports no relations have been found [15]. For TIMP-1, several studies have reported the association between high levels of TIMP-1 and poor prognosis both at the mRNA and at the protein level in breast cancer [16]. However, other studies have shown discordant results [17]. Thus, the prognostic significance of TOP2α and TIMP-1 in breast cancer remains controversial.

This study is a part of a multistage study aiming at evaluation of the prognostic and predictive significance of TOP2α and TIMP-1 in LABC. In the present study, both markers were evaluated in pretreatment needle core biopsies in an attempt to identify their association with some pretreatment clinicopathological prognostic factors.


  Patients and methods Top


This study was carried out on 84 Egyptian women with LABC diagnosed between 2003 and 2012 at the Pathology Department, National Cancer Institute, Egypt, and the Menoufia pathology department. The cases were selected on the basis of the availability of tissue blocks. All patients were subjected to needle core biopsies on which immunohistochemical staining for TOP2α, TIMP-1, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2/neu) was performed.

Clinical data

The clinical data were collected from the patients' medical records and included the following:

(1) Age of the patients (<50 and ≥50 years).

(2) Tumor stage was assessed clinically on the basis of cancer TNM classification [18].

Histopathological data

We re-evaluated the histopathological features of the hematoxylin and eosin-stained sections to confirm the diagnosis, and in addition, to determine the available prognostic and predictive features including tumor grade according to the criteria of Nottingham modification of the Bloom-Richardson system [19].

Immunohistochemistry

The streptavidin-biotin amplified system was used for immunostaining. For TOP2α, TOP2α Ab-4, Clone Ki-S1, mouse monoclonal antibody, ready to use, was applied (catalog #MS-1819-R7; Labvision, USA). Positive controls for TOP2α (normal tonsillar tissue) together with negative control (excluding the primary antibody step) were included in each run of staining.

For TIMP-1, TIMP-1 Ab-2, clone 102 D1, mouse monoclonal antibody was applied (catalog #MS-608-PCL; Labvision). It was received as 1.0 ml concentrated and diluted by PBS in a dilution of 1 : 50 according to the instructions in the pamphlet supplied. Positive controls for TIMP-1 (bladder carcinoma tissue) together with negative control (omitting of primary antibody step) were included in each run of staining.

For ER, mouse monoclonal antibody (clone 1D5, concentrated with dilution 1 : 50; Dako, UK) was applied. For PR, rabbit monoclonal antibody (clone 1A6, concentrated with dilution 1 : 50; Dako) was applied. For HER2/neu, mouse monoclonal antibody (clone 250, concentrated with dilution 1 : 100; Dako) was applied.

Interpretation of immunohistochemical staining for TOP2α and TIMP-1

Positive TOP2α expression was assigned when 10% of cells showed brown nuclear staining. [20].

Positive TIMP-1 expression was assigned when any number of cells showed diffuse brown cytoplasmic staining. The extension was scored on a scale of 0-3, where 0 indicates less than 10%; 1, 10-50%; 2, 51-75%; and 3, more than 75%. (b) The intensity was graded on a scale of 0-3, where 0, no or barely detectable signal; 1, weak signal; 2, intermediate signal; and 3, strong signal. (c) Then, combining the intensity and extension of immunoreactive cells resulted (from 0 to 6) in the final scale of 0-3 in what is called the staining index (SI). SI was used to define negative (SI ≤ 1) and positive (SI > 1) expression of TIMP-1 [21].

ER and PR immunostaining interpretation

The assessment of the immunohistochemical staining results for ER and PR was performed according to the American Society of Clinical Oncology/College of American Pathologist, where staining is considered positive if at least 1% of the tumor cell nuclei are immunoreactive [22].

HER2∕neo immunostaining interpretation

HER2/neu immunoreactivity was evaluated according to Wolff et al. [23], and only three cases were found to be positive (strong complete membrane staining is observed in >30% of tumor cells).

Molecular classification

Using the results of ER, PR, and HER2/neu receptors, the cases were stratified as a Luminal group (ER+, PR+), an HER2/neu positive group (ER-, PR-, HER2/neu+), or a triple negative group (ER-, PR-, HER2/neu-).

Statistical analysis

Data were collected, tabulated, and statistically analyzed using a personal computer with 'statistical package for the social sciences' version 16 program (SPSS 16.0.1 - November 2007, SPSS Inc. company, SPSS Ltd, Hong Kong). χ2 -test and Fisher's exact tests were used for comparison of qualitative variables. Mann-Whitney (U) and Student t tests were used for comparison of quantitative variables. A P value 0.05 or less was considered significant.


  Results Top


Clinicopathological characteristics

The age of the patient in our study ranged from 29 to 86 years, mean ± SD 53.58 ± 11.04 and median 53.5 years. With grouping, 32 cases (38%) were less than 50, whereas 52 of 84 (62%) of the cases were at least 50 [Table 1].
Table 1: Clinicopathologic data of the studied cases

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Tumor size: pretreatment tumor size was available only for 71 cases. According to the TNM staging system, seven cases (9.8%) were less than 2 cm (T1), whereas 32 cases (45.1%) were 2-5 cm (T2) and 32 cases (45.1%) were more than 5 cm (T3).

LN staging: it was available only for 69 cases. Fifty of 69 cases were N1 (72.5%), whereas nine cases were N0 (13%) and 10 cases were N2 (14.5%).

Tumor stage: all the cases studied (100%) were in the locally advanced stage.

In terms of histopathological types, all the 84 cases studied (100%) were invasive duct carcinoma (NOS).

Tumor grade: 62 of our studied cases (73.8%) were grade II, 13.1% were grade I, and 13.1% were grade III.

Mitosis: the mitotic count of the studied group ranged from 1 to 20/10 HPF, mean ± SD 6.55 ± 4.63 and median 5.

Apoptosis: the apoptotic count of the cases studied ranged from 0 to 13/10 HPF, mean ± SD 4.05 ± 2.68 and median 4.

The in-situ component: for all the studied cases, there were only 24 cases (28.6%) with an in-situ component. The type of in-situ component was the noncomedo type in 14/24 cases (58.3%) and the comedo type in 10/24 cases (41.7%).

Necrosis: Among all the studied cases, around three quarters did not show necrosis (73.8%).

Lymphovascular invasion: only 22/84 cases (26.2%) showed positive vascular invasion.

TOP2α expression

Fifty-seven of 84 cases (67.9%) showed positive TOP2α expression, with the proportion of TOP2α immunopositive cells (%score) ranging from 0 to 95%, mean ± SD of 27.84 ± 26.16% and median 25% [Figure 1].
Figure 1:

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TIMP-1 expression

Forty-eight of 84 cases (57.1%) showed positive TIMP-1 expression, with the proportion of TIMP-1 immunopositive cells (%score) ranging from 0 to 5%, mean ± SD 35.59 ± 32.93% and median 30% [Figure 2].
Figure 2:

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ER, PR, and Her2/neu immunohistochemical status

More than half of the cases, 50/84 (59.5%), were ER+, whereas 49 cases (58.3%) were PR+ and only 10 cases (11.9%) were positive for HER2/neu [Table 2].
Table 2: Immunohistochemical results of the studied cases (ER, PR, and HER2/neu)

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Molecular classification

The majority of the cases were luminal, 65.5% of all the studied cases (55 cases), whereas only seven cases (8.3%) were HER2/neu positive and 22 cases (26.2%) were triple negative [Table 3].
Table 3: Molecular classification of the studied cases

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Correlation between TOP2α expression and the studied clinicopathological parameters, hormonal, and molecular classification

We found that positive TOP2α expression was significantly associated with the presence of necrosis (P = 0.03). Furthermore, positive TOP2α cases showed higher mitotic activity, although statistical significance was not reached (P = 0.08). There was no significant correlation between TOP2α expression and the remaining clinicopathologic parameters [Table 4]. There was no significant association between TOP2α expression and ER and PR status. Although high TOP2α expression was observed in 90% of HER2/neu-positive cases, this result did not reach statistical significance. Also, there was no statistical significance in the molecular classification, although there was a tendency of 75.9% of the nonluminal cases (triple negative and HER2/neu-positive groups) to have positive TOP2α expression, but this association was not statistically significant [Table 5].
Table 4: Comparison between TOP2 a expression and clinicopathological parameters

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Table 5: Comparison between TOP2 a expression and the hormonal and molecular classification

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Correlation between TIMP-1 expression and the studied clinicopathological parameters, hormonal, and molecular classification

We found that positive TIMP-1 expression was associated significantly with a low apoptotic count (P = 0.03). There was no significant correlation between TIMP-1 expression and the remaining clinicopathologic parameters [Table 6]. There was no significant association between TIMP-1 expression and ER, PR, and HER2/neu status. Also, there was no statistical significance in terms of the molecular classification [Table 7].
Table 6: Comparison between TIMP-1 expression and clinicopathological parameters

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Table 7: Comparison between TIMP-1 expression and the hormonal and molecular classification

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  Discussion Top


LABC remains a clinical challenge because of the aggressive nature of this group of tumors and late diagnosis in Egypt [5]; in addition, the majority of patients develop distant metastasis, disease relapse, and eventual death [7]. Thus, we have attempted to identify the prognostic roles of both TOP2α and TIMP-1 in LABC.

TOP2α positivity was observed in 67.9% of our LABC cases. Our results are similar to those reported by Biesagaa et al. [24], who reported 60% positivity for TOP2α. In contrast, Fritz et al. [14] reported a lower percentage (34%) and El-Charnoubi et al. [25] reported 48% positivity. In addition, the proportion of TOP2α immunopositive cells (%score) in our study ranged from 0 to 95%, mean ± SD 27.84 ± 26.16% and median 25%. Fritz et al [14] reported that the proportion of TOP2α immunopositive cells in breast carcinomas ranged from 0.6 to 37.4%, mean ± SD 10.6 ± 7.9%, which is much lower than our result.

TOP2α is a target for a wide variety of structurally diverse cytotoxic drugs, including some of the most important anticancer drugs. Drugs targeted against TOP2α trap the enzyme in a so-called cleavable complex, thereby inhibiting its proper function [26]. This results in the accumulation of double-stranded DNA breaks, which are lethal to the cell causing apoptosis [27]. The high percentage of expression of TOP2α in LABC indicates that it may be targeted successfully in LABC cases.

In the current study, there was a significant relationship between positive TOP2α and the presence of necrosis (P = 0.03). Many studies have reported that the presence of necrosis is one of the aggressive pathologic features (poor prognostic factor) [28]. As TOP2α expression is associated with the presence of necrosis, which is a poor prognostic factor, this may indicate that TOP2α expression is associated with a poor prognosis [29]. There was also a near-significant association identified between positive TOP2α expression and high mitotic count (P = 0.08); this may indicate the association of TOP2α expression with rapidly dividing mitotically active cells and hence with a poor prognosis. This result was in agreement with that of Biesagaa et al. [24].

Although high TOP2α expression was observed in 90% of HER2/neu-positive cases, there was no statistical significance between TOP2α expression and HER2/neu overexpression. A similar result was reported by Fritz et al. [14]. In contrast, Di Leo et al. [30] reported that most of the cases that showed TOP2α expression also showed HER2/neu overexpression. Also, Jarvinen et al. [31] reported that TOP2α is preferentially expressed in a more aggressive subset of breast tumors (HER2/neu overexpressed). This may be because the TOP2α gene is located at chromosome 17q21-22 in close proximity to HER2/neu, resulting in a proportion of HER2-amplified breast cancers also containing co-amplification of TOP2α. Additional molecular techniques such as fluorescent in-situ hybridization are needed to re-evaluate two positive HER2/neu cases.

There was a tendency of 75.9% of the nonluminal cases to have positive TOP2α expression, but this association was not statistically significant. There was also no significant difference inTOP2α immunoreactivity status between ER+ and ER- cases (P = 0.36), or between PR+ and PR - cases (P = 0.12). Similar results were obtained by Glynn et al. [32], who reported that amplification levels of TOP2α did not differ significantly between luminal and nonluminal cases. They also reported that the TOP2α level did not differ significantly between patients who had been classified as ER+ and those classified as ER− (P = 0.125), or between PR+ and PR− patients (P = 0.688). Biesagaa et al. [24] also reported no significant correlation between ER+ and ER- tumors and TOP2α expression level.

The absence of TIMP-1 preclinically has been associated with increased chemosensitivity, and low levels of TIMP-1 protein have been associated with a higher probability of achieving an objective response following chemotherapy for metastatic breast cancer [33]. Many studies have proved that TIMP-1 overexpression is associated with adverse pathologic features, poor prognostic factors, and hence short survival [13]. Lipton et al. [17] and Dechaphunkul et al. [13] also reported that high TIMP-1 expression was associated with early relapse irrespective of stage, grade, hormonal, and HER2/neo status.

TIMP-1 positivity was observed in 57.1% of our cases. Our results are in agreement with those reported by Wurtz et al. [16], who reported a similar percentage for TIMP-1 positivity (60%), but Dechaphunkul et al. [13] reported a higher percentage (65%) and Kuskunoviζ et al. [21] reported 92% positivity.

In this study, there was a significant relationship between positive TIMP-1 and a low apoptotic count (P = 0.03). Our result was in agreement with that of Petit et al. [33] and Dechaphunkul et al. [13]. This confirms the antiapoptotic activity of TIMP-1 as it binds to a cell surface protein complex, including CD63 and β1 integrin, which then induces intracellular signaling cascades activating the Akt survival pathway [34]. TIMP-1 also has an intact matrix that plays a key role in the regulation of apoptosis, probably by providing a direct cell survival signal or by preventing the release of matrix-bound proapoptotic factors. The degree of apoptosis in the primary tumor might have prognostic significance. Thus, lower levels of apoptosis might lead to malignant cell accumulation and therefore to a more aggressive clinical course [28]. Also, lower apoptosis is suggested to be associated with poor response to therapy; thus, our study indicates that TIMP-1 may be associated with chemoresistance because of a significant association with decreased apoptosis [35].


  Conclusion Top


From the present study, we can conclude that TOP2αα-positive and TIMP-1-positive expression in diagnostic samples of LABC patients may be associated with factors of poor prognosis such as the presence of necrosis and low apoptotic count, respectively. Additional studies are still needed to correlate the expression of both markers with the overall survival and response to chemotherapy to confirm the prognostic and predictive roles of these markers.


  Acknowledgements Top


Conflicts of interest

None declared.

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]


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