https://orcid.org/0000-0002-0812-9592
ABSTRACT
Several studies have reported increased glucose transporters (GLUT) expression in different cancer types, including breast cancer. The primary purpose of this study is to examine GLUT1 immunoexpression in breast cancer patients in Saudi Arabia and to determine its significance. The study examined the association between GLUT1 immunophenotype and the clinicopathological characteristics in breast cancer. GLUT1 expression was analyzed in retrospectively collected tissue samples (n = 578) from breast cancer patients using immunohistochemistry. A total of 311 (54%) of the cases expressed GLUT1 cytoplasmic immunohistochemical staining. In univariate analysis, we found a significant association between GLUT1 expression and high-grade tumors (p < 0.0001). Positive estrogen and progesterone receptor results predicted lower GLUT1 immunoexpression (p < 0.0001 for both). Vascular invasion showed a significant association with GLUT1 immunoexpression (p = 0.045). Our findings support that GLUT1 immunohistochemistry can be used as a marker to determine the grade and hormonal receptor status in breast cancer.
1. Introduction
Despite the large number of studies and research, breast cancer remains a significant global health problem [Citation1]. Current development of diagnostic methods and awareness campaigns contributed to the progressive increase in breast cancer incidence around the world. Breast cancer is the most common malignancy and one of the leading causes of death in women in Saudi Arabia and worldwide [Citation1–5]. In 2018, the incidence of breast cancer among women in Saudi Arabia was 29.7% [Citation6].
Breast cancer is a heterogeneous and multifactorial disease. Genetic, environmental, and hormonal factors play roles in its pathogenesis and contribute to prognosis and management [Citation7]. Therefore, it is necessary to keep searching for more biomarkers to predict prognosis and to enhance personalized medicine and targeted therapy [Citation8].
It is recently recognized that breast cancer in Middle East is distinctive in many perspectives, including younger age at presentation, advanced disease, higher stage, and unique genetic markers. Additionally, it has been reported that BRCA1 and BRCA2 mutations in breast cancer patients in Arab countries are not as common as in other countries [Citation9,Citation10]. The high rate of consanguinity (10–67%) and the genetic diversity in Middle East contribute to these notable variabilities [Citation11,Citation12]. The establishment of the Arab genome project by different Arab countries, including Saudi Arabia, will participate in discovering new breast cancer biomarkers that help in diagnosis, target therapy development, and prognosis improvement [Citation13]. From this standpoint, we decided to examine the GLUT1 expression in Breast cancer patients in Saudi Arabia, to determine its significance and to compare our results with other studies published worldwide.
The status of hormonal receptors (HR), like estrogen hormone receptor (ER) and progesterone hormone receptor (PR), and human epidermal growth factor 2 (Her2) levels are important factors in determining the prognosis and management of breast cancer patients [Citation14,Citation15]. Triple-negative breast cancer (TNBC), which accounts for approximately 15% of breast cancer, is characterized by the lack of expression of ER, PR, or HER2 markers [Citation16]. It is considered a highly aggressive subtype with a worse prognosis, poorer overall survival rate, and higher recurrence and metastatic rate than those of Her2-positive or HR-positive breast cancer [Citation17,Citation18].
Healthy cells and cancer cells differ markedly in their metabolic features. Normal cells use glucose metabolism only in the absence of oxygen. However, cancer cells exhibit continuous glucose uptake and use regardless the oxygen supply, i.e. the Warburg effect [Citation18]. This effect is even increased in response to hypoxia and cancer progression [Citation19]. GLUT1 is one of the most widely expressed enzymes in aerobic glycolysis. It is a GLUT enzyme family member that is a solute carrier 2A (SLC2A) [Citation8,Citation20]. GLUT1 transports glucose across the cell membrane to regulate the cellular energy supply [Citation21,Citation22]. GLUT1 expression in several cancer types, including breast cancer, was found to be high to maintain the energy level and glucose required for cell proliferation, survival, and subsequent invasion. [Citation22–24] Some studies revealed that the level of expression of GLUT1 relates with the cancer grade, in which higher grade cancers were shown to have higher GLUT1 expression [Citation25]. Several studies have assessed the prognostic role of GLUT1 in breast cancer; however, their conclusions are conflicting [Citation23].
The purpose of our study was to determine whether GLUT1 immunoexpression is increased in breast carcinomas and whether the expression intensity correlates with clinicopathological factors, including patients’ age, size of the tumor, histological grade, vascular invasion, metastasis to lymph node, distant metastasis, HR status, and breast cancer-specific mortality rate. According to the authors’ knowledge, this study is the first in Saudi Arabia and Middle East to evaluate GLUT1 immunohistochemistry expression in breast carcinoma.
2. Methods
The study included 578 retrospectively collected samples from breast cancer patients who attended King Abdulaziz University Hospital (KAUH) in Jeddah, Saudi Arabia between January 1996 and December 2012. The samples were archived at the pathology department at KAUH. Relevant clinicopathological features including age, tumor histological type, tumor size, tumor grade, lymph node status, vascular invasion, hormonal receptor status, metastasis, recurrence, and breast cancer-specific mortality data were collected from patient files and summarized in . The specimens were used according to the Ethical Committee guidelines, and the institutional review board at KAUH approved the study protocol.
Table 1. Clinicopathological characteristics of breast cancer patients overall and by levels of GLUT1 immunoexpression.
2.1. Ethics approval and consent to participate
The study was approved by the Research Committee of the Biomedical Ethics Unit at our institution (Reference No 77–21). Consent was not requested as this is a retrospective study using archival material. The study was in accordance with the Declaration of Helsinki of 1975.
2.2. Tissue microarray production
Tissue microarrays (TMAs) were designed to identify appropriate regions on a patient’s tissue block (TMA Master 1.14 SP3 from Histech Ltd., Budapest, Hungary). Sections from breast cancer and positive lymph nodes were cut, stained with hematoxylin and eosin, and evaluated by an experienced pathologist. The best areas were selected, marked, and punched to obtain two cores (each measuring 1.5 mm in diameter). The two cores were then inserted into a TMA paraffin block.
2.3. Immunohistochemistry staining protocol
TMA paraffin blocks with a 4-mm diameter were cut, placed onto slides coated with a positively charged compound (Leica Microsystems Plus Slides), and then deparaffinized using xylene. Automated immunostainer was used (BenchMark XT, Ventana Medical Systems Inc., Tucson, AZ, USA). Pretreatment and dilution were performed using CC1 cell conditioning solution for 60 min.
GLUT1 rabbit polyclonal primary antibody (Ventana Medical Systems Inc.) was added to tissue sections and incubated at 37°C for 20 min. A Ventana I-view DAB detection kit (Ventana Medical Systems Inc.) was used according to kit manufacturer’s instructions. Extra stain was removed by washing, and the sample was counterstained using hematoxylin, dehydrated, and mounted on a slide using a cover slip.
Sections from placental tissue were included as a positive control. Cases with more than 5% of cells stained were considered to be positive. Two pathologists analyzed the samples using semiquantitative method. In case of disagreement between the two pathologists, the lowest score was chosen.
Scores were given as 0, 1, 2, and 3, where 0 represents negative staining, 1 represents low-level immunoreactivity, and 2 and 3 represent high level (). We merged score 2 and score 3 to improve the interpretation of the results and for parsimony. Please note that the results and conclusions of the study did not differ before and after merging the two scores.
Figure 1. Cytoplasmic expression of GLUT1 in breast cancer. a: negative stain (20X); b: weak positive stain (20 X); c: moderate positive stain (20 X); d: strong positive stain (20X).
2.4. Study variables
The information on the clinico-pathological characteristics of the subjects were collected from patients’ files. Trained pathologists determined tumor size, lymph node metastasis, histological type, tumor grade, tumor and vascular invasion, and the respective ER, PR, and HER2 status using standardized protocols. Distant metastases were inferred from clinical and pathological data.
2.5. Statistical analysis
We used the mean (standard deviation; SD) and frequency with the percentage to describe continuous and categorical variables, respectively. An analysis of variance was used to compare the means of continuous normally distributed variables. The Chi-square test was applied to compare frequency distributions of categorical variables. We used univariate ordinal logistic regression to determine the direction and magnitude of the associations between GLUT1 (none, low, and high staining) and tumor grade, ER, PR, and HER2. Additionally, the score test was used to examine the proportional odds assumption. We limited testing associations to univariate analysis due to missing values being heterogeneous among exposure variables, such that with more variables added to the model the sample size progressively gets smaller. The analyses were completed using SAS 9.4 (SAS Institute, Cary, NC, USA) with a significance level set at 0.05.
3. Results
The mean age of breast cancer patients was 50.4 ± 13.4 years. Among the 578 breast cancer tissue samples, no GLUT1 immunoexpression was detected in 46% of cases, and low and high GLUT1 expression was observed in 24% and 30% of cases, respectively.
Clinicopathological characteristics of the study participants are presented in . Tumor grade differed significantly among GLUT1 immunoexpression levels (p < 0.0001), and higher tumor grades had stronger stain. Positive ER and PR predicted lower GLUT1 immunoexpression (p < 0.0001 for both). However, HER2 was not related to the GLUT1 staining level. Vascular invasion showed a significant association with GLUT1 immunoexpression (p = 0.045). No other clinicopathological characteristics showed a significant association with GLUT1 immunoexpression.
shows the direction and magnitude of the association of characteristics that predicted GLUT1 immunoexpression. Compared with tumor grade 1, tumor grades 2 and 3 showed a direct association with GLUT1 immunoexpression (odds ratio [OR] 2.18, 95% confidence interval [CI] [1.31, 3.61] and OR 5.33, 95%CI [3.11, 9.15], respectively). ER and PR were inversely related to GLUT1 immunoexpression (OR 0.40, 95%CI [0.28, 0.58] and OR 0.42, 95%CI [0.30, 0.60], respectively).
Table 2. Odds ratios (95% CI) of the association between histopathological characteristics and GLUT1 immunoexpression level×.
4. Discussion
GLUT1 expression in different tumors, including breast carcinoma, has been investigated in several studies using different methods, but the underlying mechanism and exact contribution in malignant breast cells remains unclear and some results were inconsistent. To address this conflict, we evaluated GLUT1 expression using immunohistochemistry in 578 sections from breast cancer tissue. The aim of our study was to examine GLUT1 expression in breast cancer cases using immunohistochemistry and to identify the association between GLUT1 immunophenotype and the clinicopathological characteristics in breast cancer. In this report, we found a significant association between GLUT1 expression and breast cancer, which will add to our knowledge about breast cancer pathology and potentially identify targeted therapies.
Glucose is the dominant fuel and source of energy production in most cells. In 1924, Otto Warburg demonstrated that malignant cells depend mostly on glycolysis and also on transforming glucose to lactate, as a substitute to the normal glucose metabolism by mitochondria as well as oxidative phosphorylation [Citation18]. The high index of proliferation in malignant cells exceeded the existing vasculature, which placed the cells into a hypoxic condition that increased the required energy level. 19,27This condition induces upregulation of GLUT transcription to increase glucose uptake as a possible adaptation to reach their required high energy level [Citation25–29]. The GLUT family transports glucose across the plasma membrane to maintain the glucose level needed in cell metabolic processes [Citation30,Citation31].
The GLUT family, encoded by the SLC2A gene, consists of 14 members, and it is divided into three subfamilies according to their sequence homology [Citation32]. GLUT1 is one of the most frequently expressed isoforms [Citation33]. It is a transmembrane protein that facilitates the diffusion of glucose across the cell membrane. Normally, GLUT1 is expressed on red blood cells, endothelial cells in the blood – brain barrier, testicular germinal cells, renal tubular cells, and perineurium of peripheral nerves [Citation34–36].
Several studies have reported an increase GLUT expression in different cancer types including breast cancer. Godoy et al. evaluated the GLUT1 expression level in benign and malignant breast tissue using in situ hybridization and immunohistochemistry. They found higher GLUT1 expression in breast cancer compared to benign breast tissue [Citation33].
In our study, GLUT1 immunostaining was detected in 54% of the cases, and 25% showed low expression (score 1) while 30% showed high expression (score 2 and 3). Our study revealed there is a significant and direct association between GLUT1 immunostaining positivity and high-grade breast cancer (p < 0.0001) and a correlation with vascular invasion (p = 0.045). However, a significant inverse correlation was found between tumors with positive ER and PR and GLUT1 expression (p < 0.0001). No significant association was found between GLUT1 expression and tumor size, lymph node metastasis, HER2 status, distant metastasis, recurrence, or breast cancer-specific mortality rate. This could be due to lack of some data.
It is well known that lymph nodes status, tumor size, histologic type, grade, and hormonal receptor status are among the prognostic factors of breast cancer. The founded association between GLUT1 and some of these factors in our study, including tumor grade and hormonal status, indicates that GLUT1 has the potential to be used as a future biomarker and to predict some of the breast cancer histopathological features and phenotypes.
Our findings are similar to the results of a previous meta-analysis study, which showed that overexpression of GLUT1 is associated with a high tumor grade (p < 0.001), negative ER and PR status (p < 0.001). However, no significant association was shown between GLUT1 expression and tumor size, metastasis to lymph node, or HER2 status [Citation23].
Furthermore, Hussein et al. found that GLUT1 was expressed in 76.4% of TNBC (p < 0.001), with an overall significant association between GLUT1 expression and high histologic grade and between negative ER and PR (p < 0.001) [Citation34]. This is in agreement with Pinheiro et al. who detected significant association between GLUT1 expression and high-grade tumors (p = 0.0014) as well as the basal-like subtype (p = 0.0008) [Citation37]. These and other studies [Citation38,Citation39] also showed that GLUT1 is upregulated in TNBC, which explains the aggressive behavior and worse prognosis. This is a promising result toward discovering a targeted therapy for one of the worst types of breast carcinoma [Citation40–42].
Although our results showed no significant association with other parameters including breast cancer-specific mortality rate, lymph node metastasis, and tumor size, several studies demonstrated an association between GLUT1 expression and unfavorable overall survival, worse disease-free survival, positive lymph node metastasis, larger tumor size, and invasive ability [Citation8,Citation24,Citation35,Citation43–46]. These discrepancies can be related to the population diversity, sample size variation, and technique variability. However, our findings indicate that GLUT1 can be a good prognostic biomarker in breast carcinoma.
Our study has some limitations, including loss of tissue during processing, lack of tumor cells in some cores, univariate analysis of the data as we were unable to collect survival data and therefore we used binary outcome (breast cancer-specific mortality). Additional studies are needed to overcome these limitations and determine the role of GLUT1 in breast cancer prognosis and management.
5. Conclusion
This study supports the previous published studies and demonstrates the association between GLUT1 immunophenotype and the clinicopathological characteristics in breast carcinoma. Our findings suggest that GLUT1 could help to determine tumor grade, hormonal receptor status, and vascular invasion in breast cancer cases. Further studies are required to elucidate the role of GLUT1 in the clinical management of breast cancer.
Authors’ contributions
JAl-M Design the study and the experiments.
JAl-M, MH, AS, and SS analyzed and discussed the results, and drafted the manuscript.
All authors read and approved the final manuscript.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study was approved by the Research Committee of the Biomedical Ethics Unit at King Abdulaziz University (Reference No 77–21), and it waived the informed consent as it was a retrospective study using archival material.
Acknowledgments
The authors acknowledge with thank Gladys Harder, Department of Pathology, King Faisal Specialist Hospital, Jeddah, Saudi Arabia, for technical support.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
References
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