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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 39  |  Issue : 1  |  Page : 212-227

GATA-binding protein 3 and androgen receptor expressions in invasive breast cancer: the relationship with molecular phenotypes, disease progression, and survival outcomes


1 Department of Pathology, Faculty of Medicine, Minia University, Egypt
2 Department of Pathology, Minia Oncology Center, Minya, Egypt

Date of Submission15-Apr-2019
Date of Acceptance31-Jul-2019
Date of Web Publication29-Nov-2019

Correspondence Address:
Manal I Abd-Elghany
Department of Pathology, Faculty of Medicine, Minia University, Minya, 61111
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/EGJP.EGJP_26_19

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  Abstract 


Breast cancer (BC) is considered as one of the most frequent cancers worldwide. GATA3 plays a crucial role in promoting proliferation and differentiation in many tissues including breast. Loss of GATA3 expression in BC has been associated with aggressive tumors and poor prognosis. Androgen receptor (AR) has been reported to be involved in differentiation, development, and regulation of breast cell growth. The aim of this study was to investigate the immunohistochemical expressions of GATA3 and AR and their relationships with different clinicopathological features and molecular phenotypes and to further evaluate their prognostic significance. Immunohistochemical expressions of GATA3 and AR were evaluated in 61 formalin-fixed and paraffin-embedded tissue specimens of invasive duct carcinoma. Positive GATA3 immunostaining was detected in 54.1% of cases and showed significant associations with lower tumor grade (P=0.007), estrogen receptor (ER)-positive expression (P=0.000), progesterone receptor-positive expression (P=0.001), and good and moderate Nottingham prognostic index (P=0.012). No significant relationship was found between GATA3 expression and other clinicopathological parameters. Positive AR expression was detected in 60.7% of cases and showed positive significant associations with lower tumor grade (P=0.005), ER-positive expression (P=0.0001), progesterone receptor-positive expression (P=0.001), and good and moderate Nottingham prognostic index (P=0.011). No significant relationship could be found between AR expression and other clinicopathological features. Higher rates of positive GATA3 and AR expressions were observed in luminal A and luminal B phenotypes, but negative expressions of GATA3 and AR were observed frequently in HER2 and triple-negative breast cancer subgroups (P=0.001 and 0.001, respectively). To determine the immunoprofile of the examined tumors, cases were stratified according to the joint expression status of GATA3 and AR. This study has found a highly significant positive correlation between the expressions of GATA3 and AR (r=0.99, P<0.0001). Univariate survival analyses demonstrated that cases expressing positive GATA3 and AR had a significantly longer relapse-free survival and better clinical outcomes than those with negative expressions (log-rank P=0.0000 and ˂0.0001, respectively). Cox multivariate regression analysis has selected ER (P=0.015), stage (P=0.014), AR (P=0.003), and combined GATA3/AR immuonoexpressions (P=0.048) as independent prognostic indicators. Altogether, our findings suggest that AR and combined GATA3/AR immunoexpressions can serve as independent good prognostic biomarkers in BC.

Keywords: androgen receptor, GATA3, invasive duct carcinoma, molecular classification


How to cite this article:
Abd-Elghany MI, El Zahraa AMohamed F, Toni ND, Boshra MS. GATA-binding protein 3 and androgen receptor expressions in invasive breast cancer: the relationship with molecular phenotypes, disease progression, and survival outcomes. Egypt J Pathol 2019;39:212-27

How to cite this URL:
Abd-Elghany MI, El Zahraa AMohamed F, Toni ND, Boshra MS. GATA-binding protein 3 and androgen receptor expressions in invasive breast cancer: the relationship with molecular phenotypes, disease progression, and survival outcomes. Egypt J Pathol [serial online] 2019 [cited 2020 Jan 28];39:212-27. Available from: http://www.xep.eg.net/text.asp?2019/39/1/212/272004




  Introduction Top


Breast carcinoma (BC) is a major global problem, with nearly 1.7 million new cases diagnosed among women worldwide each year (International Agency for Research on Cancer, 2016). It is considered the second leading cause of carcinoma-related death (15%) after lung carcinoma (Baade, 2017) and accounts for 458 000 deaths each year (Altobelli, 2017). The worldwide incidence of BC is higher in developed countries than in middle- and low-income countries (Youlden et al., 2012; International Agency for Research on Cancer, 2016).

Invasive ductal carcinoma (IDC) is the most common type of invasive BC, accounting for 65–80% of invasive BC (Suryadevara et al., 2010). BC is no longer a single disease, but it is a heterogeneous disease consisting of different phenotypes on the molecular and histopathological levels with variable prognostic and therapeutic outcomes (Foukakis and Bergh, 2015; Thakkar et al., 2015; Effi et al., 2016; Falck et al., 2016; Samaka and Younes, 2016; Mota et al., 2017; Asano et al., 2017).

Despite the advanced genetic diagnostic methods, the management of BC still depends on standard clinicopathologic prognostic factors associated with immunohistochemical (IHC) expressions of estrogen receptor (ER)/progesterone receptor (PR) and HER2 (Effi et al., 2016; Mota et al., 2017; Errahhali et al., 2017). However, the complete cure from BC is still not achieved, and better understanding of the molecular background of it may hopefully lead to successful and complete cure. Unfortunately, the etiology of BC is still not fully understood, but a variety of factors have been identified to influence its development, one of them being the genetic factor (Ferlay et al., 2010). Recently, GATA was identified as a key regulator of luminal cell lineage differentiation from mammary stem cells and maintenance of differentiated luminal epithelium within the mature gland (Guo et al., 2017; Lin et al., 2017).

GATA3 is one of the six members of a zinc finger transcription factor family, and it plays an important role in promoting cell proliferation, development, and differentiation in many tissues (Guo et al., 2017; Lin et al., 2017; Yang et al., 2017). In addition, GATA3 has been shown to be important in the context of BC and the ERα pathway. Recently, it was demonstrated that GATA3 is required for estradiol stimulation of cell-cycle progression of BC cells (Thakkar et al., 2015; Yang et al., 2017). Thus, understanding the role of GATA3 in BC can be a promising potential target in BC management.

It is well known that BC is one of the hormone-dependent tumors, and its relationship with ER and PR has prognostic values (Goyanes et al., 2010; Effi et al., 2016). Interestingly, both androgens and estrogens bind to steroid hormone-binding globulin in the circulation, which controls the bioavailability of hormones to the breast and other tissues (McNamara et al., 2014; Aleskandarany et al., 2016). Although androgens are commonly considered as male hormones, they are also detected at physiological low levels in the circulation of women and play important biological roles in women (McNamara et al., 2014; Pietri et al., 2016).

AR is a ligand-dependent transcription factor that controls the expression of specific genes involved in many physiological and pathological processes (Higa and Fell, 2013).

Although AR is the main biological driver and therapeutic target in patients with prostate cancer (Pietri et al., 2016), its therapeutic targeting has been found to pose an antiproliferative action in patients with BC, and the use of androgens as hormonal therapy in BC has shown results that are generally comparable to tamoxifen (Aleskandarany et al., 2016; Zakaria et al., 2016). Moreover, treatment with AR antagonists in AR-expressing BCs is currently underway for clinical application (Zakaria et al., 2016).

AR expression has the potential to predict disease progression and duration of response to therapy (McNamara et al., 2014; Aleskandarany et al., 2016; Pietri et al., 2016).

Therefore, understanding the role of GATA3, the luminal cell regulator, as well as the desperate need to find a reliable prognostic marker and a new therapeutic target in BC, was beyond our strategy to select GATA3 and androgen receptor (AR) to conduct this study by investigation of their expressions by immunodetection and further to evaluate their prognostic significance in a series of invasive duct BC.


  Patients and methods Top


Patients and tissue specimens

This retrospective study was conducted on 61 formalin-fixed paraffin-embedded invasive duct BC tissue samples of Egyptian patients with BC. They were retrieved from the archives and databases of pathology laboratories of Minia Oncology Center and Pathology Department, Faculty of Medicine, Minia University, in the time interval between 2012 and 2016. Clinical data were retrieved from patients’ medical records. The clinicopathological data of the patients are summarized in [Table 1].
Table 1 Clinicopathological features for patients included in this study

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Included cases were mastectomy specimens from patients who did not receive chemotherapy before, with known status for the panel of markers including ER, PR, and HER2/neu. The frequency of positivity for each marker alone and in various combinations with any and all of the other markers was recorded.

Histological grading was done according to Scarff–Bloom–Richardson grading system (Tavassoli and Devilee, 2003). Tumors were staged according to AJCC staging system (AJCC, 2017).

Molecular subtypes were classified according to St Galen Consensus 2013 (Goldhirsch et al., 2013). The study population was classified into four BC subtypes based on ER, PR, and HER2 status into luminal A (HR-positive, HER2-negative), luminal B (ER-positive, PR-positive and HER2-positive), HER2-enriched (ER-negative, PR-negative and HER2-positive), and triple negative (ER-negative, PR-negative and HER2-negative). The Ki-67 labeling index was not included in our study, as it has been reported that its use has some limitations including lack of reproducibility, arbitrary choice of antibodies, variable methods of scoring, discrepancies regarding the optimal cutoff point as well as the potential problems that may arise owing to heterogeneity of tumors examined (Dowsett et al., 2011; Polley et al., 2015).

Nottingham prognostic index (NPI) formula was calculated as follows: NPI=0.2×tumor size (cm)+lymph node stage+histological grade (Galea et al., 1992).

Survival data included BC-specific survival in months (8–48 months), estimated from the date of diagnosis to the time of relapse (relapse free survival, RFS). An event was defined as any BC relapse (locoregional or distant), and patients were censored at the date of relapse or the date of last follow-up.

Immunohistochemistry

Four-μm-thick tissue sections were deparaffinized in two changes of xylene, then rehydrated in descending grades of alcohol (99, 95, and 70% for 2 min each). Endogenous peroxidase activity was blocked by incubation with 0.3% hydrogen peroxide/methanol for 30 min at room temperature. Antigen retrieval was performed by pretreatment of tissue sections in citrate buffer solution (pH 6) for 10 min in a microwave, at 750 W. Sections were incubated with 5% bovine serum albumin (w/v) in PBS for 30 min to block nonspecific antibody binding. Then, sections were subsequently incubated overnight at 4°C, with the primary antibody against GATA3 polycolonal mouse antibody (diluted at 1 : 100; Biocare Medical, Pacheco, CA, USA) or androgen polyclonal mouse antibody (diluted at 1 : 50; Thermo Scientific, ThermoFischer Scientific, Waltham, MA, USA). Secondary biotinylated antibody (Lab Vision Laboratories, Thermo Fisher Scientific, Fremont, CA, USA) was added for each slide for 30 min at room temperature. This was followed by incubation of slides with streptavidin reagent for 30 min at room temperature. Then, identification of bound peroxidase activity was done by incubation with a freshly prepared diaminobenzidine tetrachloride substrate and chromogen solution. Finally, slides were rinsed thoroughly in distilled water, lightly counterstained with Harris hematoxylin, dehydrated in ascending grades of ethanol, cleared in xylene, and mounted with DPX.

Urothelial carcinoma and prostate carcinoma were used as positive controls for GATA3 and AR expressions, respectively.

Assessment of immunostaining

Assessment of immunostaining was done independently by three pathologists (M.I.A., F.A.M., and N.M.T.) without previous knowledge of the clinical or pathological data of the cases. The correlation among them was high, and when discrepancies existed, a consensus was achieved by the observers evaluating the sections together.

The immunostaining expressions of GATA3 and AR were evaluated as the percentage of positively stained tumor cells in a maximum of 1000 cells per tissue section. Cases were considered positive when more than 10% of the cells showed nuclear expression for GATA3 (Tominaga et al., 2012; Hattori et al., 2015) and for AR (Niemeier et al., 2010; Park et al., 2010; Mohammed and Khaled, 2014; Zakaria et al., 2016).

Statistical analysis

Statistical analysis was conducted using the statistical package for the social sciences (SPSS software version 16, SPSS Inc., Chicago, IL, USA). Raw data were compiled and used to determine the mean±SD, median, and range of various features. The χ2 and Fisher’s exact tests were used to compare categorical variables. Pearson’s correlation coefficient or Spearman’s rank tests has been used to determine the correlations between variables. P value of less than 0.05 was considered significant.

In univariate survival analysis, RFS or distant metastasis was estimated as the end points of follow-up. Kaplan–Meier curves were used for plotting of survival data. Significant differences in survival outcomes were assessed using log-rank test. The Cox multivariate regression analysis was used to analyze the hazard ratio and the prognostic significance of GATA3 and AR.


  Results Top


Immunohistochemical expressions of GATA3 and androgen receptor

In this study, a positive nuclear GATA3 expression was detected in 33/61 (54.1%) cases, whereas 22/61 (45.9%) cases showed negative expression ([Figure 1],[Figure 2],[Figure 3],[Figure 4]).
Figure 1 Positive nuclear GATA3 expression in grade II IDC (IHC, streptavidin-biotin-immunoperoxidase, original magnification ×200). IDC, invasive ductal carcinoma; IHC, immunohistochemical.

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Figure 2 Positive GATA3 expression in in-situ cribriform component (IHC, streptavidin-biotin-immunoperoxidase, original magnification ×400). IHC, immunohistochemical.

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Figure 3 Positive GATA3 expression in grade II IDC with in-situ component (IHC, streptavidin-biotin-immunoperoxidase, original magnification ×200). IDC, invasive ductal carcinoma; IHC, immunohistochemical.

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Figure 4 Negative GATA3 expression in grade III IDC (IHC, streptavidin-biotin-immunoperoxidase, original magnification ×200). IDC, invasive ductal carcinoma; IHC, immunohistochemical.

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Regarding AR immunoexpression, positive nuclear expression was observed in 37/61 (60.7%) cases and negative expression was detected in 24/61 (39.3%) cases ([Figure 5],[Figure 6],[Figure 7],[Figure 8]).
Figure 5 Positive AR expression in grade II IDC (IHC, streptavidin-biotin-immunoperoxidase, original magnification ×400). AR, androgen receptor; IDC, invasive ductal carcinoma; IHC, immunohistochemical.

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Figure 6 Positive AR expression in in-situ component (IHC, streptavidin-biotin-immunoperoxidase, original magnification ×200). AR, androgen receptor; IHC, immunohistochemical.

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Figure 7 Positive AR expression in grade II IDC and adjacent normal glands (IHC, streptavidin-biotin-immunoperoxidase, original magnification ×200). AR, androgen receptor; IDC, invasive ductal carcinoma; IHC, immunohistochemical.

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Figure 8 Negative AR expression in grade III IDC (IHC, streptavidin-biotin-immunoperoxidase, original magnification ×200). AR, androgen receptor; IDC, invasive ductal carcinoma; IHC, immunohistochemical.

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Relationships of GATA3 and androgen receptor expressions with clinicopathological features

Correlation of the IHC expression of GATA3 was performed with different clinicopathological features, as shown in [Table 2].
Table 2 Associations between GATA3 expression and clinicopathological features for patients with invasive ductal carcinoma (n=61)

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A significant inverse relationship was found between GATA3 expression and NPI (P=0.012).

A significant positive association was found between expression of GATA3 and lower tumor grade (P=0.007), ER expression (P=0.000), and PR expression (P=0.001).

No significant relationship could be detected between GATA3 and patient age (P=0.242), tumor size (P=0.27), menopausal status (P=0.9), lymph node status (P=0.8), tumor stage (P=0.18), presence of in-situ component (P=0.113), or HER2/neu expression (P=0.7).

With respect to AR, the associations between its immunoexpression and different clinicopathological features are summarized in [Table 3].
Table 3 Associations between androgen receptor expression and clinicopathological features for patients with invasive ductal carcinoma (n=61)

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A significant inverse relationship was found between AR expression and NPI (P=0.011) and stage (P=0.036).

Significant positive associations were found between expression of AR and lower tumor grade (P=0.005), ER expression (P=0.000), and PR expression (P=0.001).

No significant relationship could be detected between GATA3 and patient age (P=0.224), tumor size (P=0.5), menopausal status (P=0.9), lymph node status (P=0.56), presence of in-situ component (P=0.4), or HER2 expression (P=0.77).

Correlations of GATA3 and androgen receptor with molecular subtypes

A significant association was found between IHC expression of GATA3 and molecular classification (P=0.001). In luminal A group, positive GATA3 expression was observed in 19/25 (76%) cases and 6/25 (24%) cases showed negative expression. In luminal B group, 12 of 16 (75%) cases displayed positive GATA3 expression and four 16 (25%) cases showed negative expression. On the contrary, in HER2-enriched type, positive GATA3 immunoreactivity was observed in one (12.5%) of eight cases, whereas seven (87.5%) of eight cases were negative. In triple-negative breast cancer group (TNBC), only one (8.3%) case of 12 cases expressed positive GATA3 expression and 11 (91.7%) of 12 cases showed negative immunostaining.

With respect to AR expression, a highly significant association was found between it and molecular subgroups (P=0.001). In luminal A group, positive AR expression was observed in 22/25 (88%) cases and negative expression was detected in only 3/25 (12%) cases. In luminal B group, 13/16 (81.2%) displayed positive AR expression and 3/16 (18.8%) showed negative expression, whereas in HER2/neu type, positive AR expression was observed in only one (11.1%) case of nine cases and negative expression was detected in 8/9 (88.9%). In TNBC, 1/11 (9.1%) cases displayed positive AR immunostaining and 10/11 (90.9%) cases showed negative expression.

Relationships between combined GATA3/androgen receptor immunoexpressions and clinicopathological features

The associations between the combined immunoexpressions of GATA3/AR and different clinicopathological features are summarized in [Table 4].
Table 4 Associations between combined GATA3 and androgen receptor immunoexpressions and clinicopathological features for patients with invasive ductal carcinoma (n=61)

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A significant inverse relationship was found between combined GATA3/AR immunoexpressions and NPI (P=0.041).

A significant positive association was found between joint immunoexpressions of GATA3/AR and lower tumor grade (P=0.023), ER expression (P=0.000), PR expression (P=0.000), and molecular subtypes of BC (P=0.000).

No significant relationship could be detected between combined immunoexpressions of GATA3/AR and either patient age (P=0.898), tumor size (P=0.681), menopausal status (P=0.957), lymph node status (P=0.642), tumor stage (P=0.313), presence of in-situ component (P=0.077), or HER2/neu expression (P=0.888).

Survival analyses

Univariate survival analyses

Univariate survival analysis revealed that patients identified with positive GATA3 expression had significantly longer survival and better outcome, when compared with patients who had negative GATA3 expression (log-rank P=0.000; [Figure 9]).
Figure 9 Correlation of GATA3 expression and survival in patients diagnosed with invasive duct carcinoma (Kaplan–Meier curve) (log-rank P=0.000).

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Regarding AR, univariate survival analysis revealed that patients with cancers expressing AR had significantly longer RFS and better clinical outcome, when compared with patients who had negative AR expression (log-rank P=0.000; [Figure 10]).
Figure 10 Correlation of AR expression and survival in patients diagnosed with invasive duct carcinoma (Kaplan–Meier curves) (log-rank P=0.000). AR, androgen receptor.

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In univariate survival analysis, the combined expressions of GATA3/AR showed a highly significant correlation with survival outcome (P=0.000; [Figure 11]). Among the four groups, GATA3 positive/AR positive group of patients had the longest RFS and best clinical outcome. On the contrary, GATA3 negative/AR negative group of patients had the shortest disease-free survival and worst outcome.
Figure 11 Correlations of the joint immunoexpressions of GATA3 and AR and relapse-free survival in patients diagnosed with invasive duct carcinoma (Kaplan–Meier curves) (log-rank P=0.000). AR, androgen receptor.

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Cox multivariate regression analyses

In the first round of selection, tumor grade, size, lymph node, and HER2/neu were excluded as they did not reach significance by univariate analysis ([Table 5]). Accordingly, Cox multivariate regression model has been done, controlling for the conventional indicators ER, PR, and stage as confounders.
Table 5 Univariate survival analysis

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In one model that included GATA3, multivariate regression analysis has selected it as an independent prognostic indicator (P=0.003; [Table 6]).
Table 6 Cox multivariate regression analysis for GATA3

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In a separate model, multivariate regression analysis has detected AR to be a strong independent prognostic indicator (P≤0.0001; [Table 7]).
Table 7 Cox multivariate regression analysis for androgen receptor

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In another model, Cox multivariate regression analysis has confirmed that the combined immunoexpressions of GATA3/AR to be an independent prognostic indicator (P=0.002; [Table 8]).
Table 8 Cox multivariate regression analysis for combined GATA3 and androgen receptor immunophenotypes

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A final analysis ([Table 9]) was performed to identify the best predictors investigated in our study. A stepwise procedure has selected ER (P=0.015), stage (P=0.014), AR (P=0.003), and combined immunoexpressions of GATA3/AR (P=0.048) as independent prognostic indicators, whereas PR and GATA3 did not reach significance.
Table 9 Final Cox multivariate regression analysis to detect the best prognostic indicators investigated in our study

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Correlation between GATA3 and androgen receptor expressions

A highly statistically significant positive correlation was found between expressions of GATA3 and AR (P<0.0001 and r=0.99), as shown in [Figure 12].
Figure 12 Correlation between immuonoexpressions of GATA3 and AR in IDC (r=0.99, P<0.0001). AR, androgen receptor; IDC, invasive ductal carcinoma.

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  Discussion Top


Despite the recent improvement of BC survival, therapeutic failure, local recurrence, and distant metastasis still represent major challenges (Wu et al., 2012). Therefore, exploring novel breast-specific markers is crucial to predict the responsiveness of treatment and potential target therapies.

In this study, we found that 54.1% of cases were GATA3 positive, whereas 45.9% showed negative expression. Overexpression of GATA3 was significantly inversely associated with tumor grade, presence of local recurrence, and good and moderate NPI. Such results were in agreement with those detected in other studies (Voduc et al., 2008; Liu et al., 2012; Tominaga et al., 2012; Hisamatsu et al., 2015; Thakkar et al., 2015; Guo et al., 2017; Yang et al., 2017).

The frequency of cases with GATA3-positive expression decreased with increasing stage. However, such relationship did not reach significance, a result that was in conformation with what was found by others (Tominaga et al., 2012; Cimino-Mathews et al., 2013). Moreover, we did not find significant correlations between GATA 3 expression and either lymph node metastasis or tumor size. Such results were in agreement with Voduc et al. (2008), and Yang et al. (2017). On the contrary, Mehra et al. (2005); Tominaga et al. (2012); and Guo et al. (2017), found a significant relationship between GATA3 and tumor size. Moreover, Mehra et al. (2005) stated that most GATA3-positive BC inversely associated with metastasis and were lymph node negative. These different results may be owing to variable sample size, different stages of the disease in the selected cases, and different cohort types.

With respect to hormone receptors’ expression, GATA3 was almost exclusively expressed in ER-positive and PR-positive tissue samples examined in our study. Such findings were in agreement with Mehra et al. (2005); Voduc et al. (2008); Liu et al. (2012); Tominaga et al. (2012); Hattori et al. (2015); Hisamatsu et al. (2015); and Guo et al. (2017). This significant positive association can be explained by that GATA3 is integral to the ER pathway and the highest co-expressing gene for GATA3 was ER and vice versa (Eeckhoute et al., 2007; Wilson and Giguere, 2008; Thakkar et al., 2015).

In agreement with some previous studies, we found no significant associations between GATA3 and HER2/neu (Tominaga et al., 2012; Hisamatsu et al., 2015; Guo et al., 2017). Conversely, a significant correlation between low GATA3 and HER2/neu overexpression was detected by Mehra et al. (2005). Moreover, HER2-positive patients had poor prognosis and reduced disease-free survival (Rakha et al., 2007; Siadati et al., 2015). However, these studies focused on investigation of ER-negative BC.

In this study, a high rate of positive GATA3 expression was observed in 76.0 and 75.0% of luminal A and luminal B groups, respectively, a finding that was similar to what was reported in other studies (Tominaga et al., 2012; Hisamatsu et al., 2015). Such association of GATA3 with luminal subtypes is consistent with its role as a master gene for luminal differentiation (Guo et al., 2017; Lin et al., 2017). Moreover, a tumor-suppressive role of GATA3 in hormone-sensitive BC has been suggested (Lin et al., 2017).

On the contrary, we found negative GATA3 expression in 87.5 and 91.7% in HER2/neu and TNBC phenotypes, respectively. These results were consistent with those found in other studies (Albergaria et al., 2009; Yang and Nonaka, 2010).

The importance of such molecular classification is derived from being must be considered to determine indicators for the use of adjuvant chemotherapy in the treatment of HR-positive/HER2-negative patients (Goldhrisch et al., 2013). Lin et al. (2017) added that these results suggest that GATA3 can provide a productive strategy in relation to its cost by identifying patients who may not require adjuvant chemotherapy. Importantly, on revision of the eighth edition of TNM classification, it has been reported that the recognition of the prognostic values of grade, hormone receptors, and HER2 expressions mandated their inclusion in the staging system (Giuliano et al., 2017). They confirmed that tumor markers and low oncotype DX recurrence score can change prognosis and stage.

In univariate survival anlysis, we found that positive GATA3 expression was expressed in cases with longer RFS and better clinical outcome. On performing multivariate analysis (after stratification for conventional prognostic indicators ER, PR, and stage), GATA3 was selected to be an independent prognostic indicator. These findings were similar to what was reported in other studies (Mehra et al., 2005; Voduc et al., 2008; Tominaga et al., 2012; Hisamatsu et al., 2015; Thakkar et al., 2015; Guo et al., 2017; Yang et al., 2017). Collectively, what has been found in this study and those reported in other studies suggests further investigations to confirm the role of GATA3 as a marker of good prognosis that may be used as a predictor for RFS and overall survival outcomes.

In this study, AR-positive expression was detected in 60.7% of examined cases, a result that was in accordance with results of other studies (Agoff et al., 2003; Niemeier et al., 2010; Pietri et al., 2016). Even other studies revealed higher frequency of AR expression (Gonzalez et al., 2008; Hattori et al., 2015).

This study showed significant negative correlations between AR expression and higher tumor grade, poor NPI, local recurrence, and presence of metastasis. These findings were consistent with many previous studies (Schippinger et al., 2006; Gonzalez et al., 2008; Peters et al., 2009; Seung et al., 2009; Niemeier et al., 2010; Collina et al., 2016; Kim et al., 2016; Maeda et al., 2016; Samaka and Younes, 2016). On the contrary, only a few studies reported positive correlations (Moinfar et al., 2003; Micello et al., 2010). Variable results could be attributed to biological differences, variable sample size, and different cutoff scoring of results.

This study found a negative significant correlation between positive AR expression and tumor stage, which was consistent with other studies (Aleskandarany et al., 2016; Zakaria et al., 2016). However, a few studies disagreed with these findings (Agoff et al., 2003; Park et al., 2010. On the contrary, we did not find a significant association between AR expression and either lymph node metastasis or tumor size. However, our results showed that the highest frequency of AR-positive expression was detected in lymph node-negative group. Our results were similar to several studies, such as Narita et al. (2006); Park et al. (2010); Qi et al. (2012); Kayahan et al.; Collina et al. (2016); Samaka and Younes (2016); and Asano et al. (2017). Variability in the published results regarding AR may be attributed to the heterogeneity of invasive BC, using different antibodies with different clones, and the variation in interobserver interpretation of immunostaining.

In this study, AR expression has a positive significant relationship with ER- and PR-positive expressions. These results were in agreement with Park et al. (2010); Hattori et al. (2015); and Samaka and Younes (2016). This relationship between AR and hormone receptor expressions may be explained by that AR belongs to the nuclear steroid hormone receptor family, which shows high structural, functional, and topographic similarity to ER and PR (Agrawal et al., 2008; Ogawa et al., 2008; Park et al., 2010).

We found no significant relationship between AR expression and HER2. However, other studies found a significant relationship between low AR expression and HER2 overexpression (Agoff et al., 2003; Niemeier et al., 2010). These variable results can be explained on the basis that the latter studies limited their investigations to ER-negative BC only. The percentages of AR-positive expression in HER2 type and TNBC types were 11.1 and 8.3%, respectively, which was in alignment with many other reports (Moinfar et al., 2003; Rakha et al., 2007; Micillo et al., 2010; Park et al., 2010; Safarpour and Tavassoli, 2014).

Overexpression of AR was significantly higher in luminal A (88%) and luminal B (81.2%) molecular types when compared with HER2/neu-positive and TNBC subtypes. Such results were consistent with those reported by Niemeier et al. (2010); Kayahan et al. (2014); Samaka and Younes (2016); and Qi et al. (2012). Collectively, our results support what has been suggested that AR is dependent on ER status. It has been reported that AR acts in the presence of ER by blocking downstream target genes of estrogen, leading to suppression of ER-induced neoplastic proliferation (Aleskandarany et al., 2016).

In this study, AR was expressed in 8.3% of TNBC phenotype cases. TNBC is known for its aggressive tumor growth and rapid spread, and patients diagnosed with TNBC often receive chemotherapy, which is considered the only remedy for it (Rakha et al., 2007). However, recent research reported that TNBC can be further classified according to its genetic profile. AR-positive TNCB is one of these subtypes. AR-positive TNBC retains androgenic signaling that could be a possible therapeutic target (Gucalp and Traina, 2010). Asano et al. (2017) suggested that AR expression may be useful as a subclassification marker for prognosis in TNBC, and AR-positive TNBCs may be responsive to antiandrogen endocrine therapy. Recently, several agents have been shown to target AR-positive cancer cells (McNamara et al., 2014).

In this study, univariate survival analysis revealed that patients with cancers expressing AR had significantly longer RFS and better clinical outcome and less aggressive behavior, when compared with patients who had negative AR expression. Moreover, cases displaying AR-negative expressions were associated with a higher recurrence rate and/or presence of distant metastasis. Furthermore, by performing multivariate regression analysis, AR has been shown to be a strong independent prognostic indicator. These findings were in agreement with other previous studies (Vera-Badillo et al., 2014; Aleskandarany et al., 2016; Kim et al., 2016; Zakaria et al., 2016; Asano et al., 2017; Erdis et al., 2017). The results of our study and those reported in other studies suggest that AR can be used as a marker of good prognosis and can serve as a predictor for RFS and overall survival outcomes.

This study next analyzed the immunoprofile of tumors investigated by stratification of cases according to the combined or joint immunoexpressions of GATA3 and AR. Interestingly, there was a significant positive associations between combined expressions of GATA3/AR and lower tumor grade, ER expression, PR expression, and molecular subtypes of BC. On the contrary, a significant inverse relationship was found between combined GATA3/AR immunoexpressions and NPI. No significant relationship could be detected between combined immunoexpressions of GATA3/AR and either patient age, tumor size, menopausal status, lymph node status, tumor stage, presence of in-situ component, or HER2/neu expression. Then, a univariate survival analysis was performed. As expected, the combined expressions of GATA3/AR had a highly significant correlation with survival outcome, where GATA3 positive/AR positive group of patients had the longest RFS and best clinical outcome, whereas GATA3 negative/AR negative group of patients had the shortest disease-free survival and worst outcome.

In this study, a final Cox multivariate regression analysis has selected ER, stage, AR, and combined immunoexpressions of GATA3/AR as independent significant indicators. The relationship among GATA3, AR, and hormone receptors are worthwhile. Full understanding of different molecular mechanisms between AR and GATA3 signaling pathways and further evaluation of the beneficial clinical implications of these biomarkers on prognosis may lead eventually to introduction of effective therapeutic strategies that may improve the survival outcomes of patients with BC.

In this study, a highly significant positive correlation was detected between the expression of GATA3 and AR, a finding that was similar to what was found in a previous study (Kim et al., 2016). In that study, which was conducted on TNBC only, it has been found that coexpression of AR and GATA3 was a specific feature of molecular apocrine-type TNBC, a finding that was recommended to serve as a diagnostic aid for cancer of unknown primary. In the literature, only a few studies have investigated the correlation between AR and GATA3 in BC. One recent study has focused on the evaluation of the prognostic significance of AR and its possible relationship with a panel of markers including GATA3, but without any discussion to the later role, significance, or its relationship with either clinicopathological features or survival outcome (Aleskandarany et al., 2016). In that study, it has been reported that AR expression was associated with markers recognized to be regulated through ER and frequently expressed in luminal molecular subtypes such as GATA3, FOX1, CARM1, RERG, PELP1, AGTR1, CD71, and BEX1. In another study, the expression patterns of GATA3 and AR have been investigated but for diagnosis of metastatic BC to the lung (Hattori et al., 2015). To the best of our knowledge, this is the first study conducted in a series of Egyptian patients with BC to investigate the relationship between the individual as well as combined expressions of GATA3 and AR and different molecular subtypes and disease progression.


  Conclusion Top


This study has demonstrated that both GATA3 and AR immunostaining levels were significantly higher in cases with favorable prognostic parameters including low tumor grades, lack of recurrence, absence of distant metastasis, good-moderate NPI, and positive ER and PR hormone receptors. In addition, significant correlations have been detected between AR and GATA3 and BC molecular phenotypes, where significant overexpressions of GATA3 and AR were observed exclusively in luminal A and luminal B molecular subtypes. Conversely, higher rates of negative expressions were detected in HER2-positive and TNBC phenotypes. The later findings support the recent recommendation that AR expression may be useful as a subclassification marker for prognosis in TNBC. The utility of AR as a therapeutic target in AR-positive BC deserves further investigations, as a recent research study has shown that AR targeted therapy in ER/PR-negative tumors may provide an economical alternative to the high-dose chemotherapy and trastuzumab. Moreover, our results suggest that GATA3 can provide a cost-effective strategy by identifying patients who can escape adjuvant chemotherapy. In this study, patients identified with positive GATA3 and AR expressions had significantly longer RFS and better clinical outcomes than those patients with negative expressions. Moreover, our results have found that AR and combined GATA3/AR immunoexpressions to be independent prognostic indicators. The results of this study suggest that testing for GATA3 and AR can hold significant effect in BC prognosis, if employed in standard clinical practice.[66]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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