Research ArticleClinical Studies

Clinical Significance of Serglycin Expression in Human Breast Cancer Patients

KEIKO HOSOYA, KANAE NOSAKA, TOMOHIKO SAKABE, MAKOTO WAKAHARA, YUKI OSHIMA, YOSHIMASA SUZUKI, HIROSHIGE NAKAMURA and YOSHIHISA UMEKITA
Anticancer Research January 2022, 42 (1) 279-285; DOI: https://doi.org/10.21873/anticanres.15483

Abstract

Background/Aim: Serglycin plays a crucial role in the aggressiveness of several types of malignancies, including breast cancer. In this study, we aimed to investigate the prognostic impact of serglycin expression in breast cancer patients, which has not been previously reported. Patients and Methods: Immunohistochemical analyses were performed on 348 resected specimens of invasive carcinomas, using antibodies against serglycin. Results: Low serglycin expression was observed in 23% of specimens (80/348) and significantly correlated with high histological grade (p=0.001) and negative ER (p=0.013). The log-rank test showed that low serglycin expression correlated with shorter distant metastasis-free survival (DMFS) (p=0.016) and disease-specific survival (DSS) (p=0.037) in node-positive breast cancer patients. Cox’s multivariate analysis revealed that low serglycin expression was an independent factor for shorter DMFS (p=0.017) and DSS (p=0.020) in node-positive breast cancer patients. Conclusion: Low serglycin expression is an independent predictor of unfavorable prognosis in node-positive breast cancer patients.

Key Words:

Breast cancer is a major health problem in women, with approximately 1.7 million new cases and nearly 535,000 breast cancer-related deaths in 2016 worldwide (1). Breast cancer is a heterogenous disease with genotypic and phenotypic diversities, and its categorization into four main breast cancer subtypes, luminal A-like, luminal B-like, HER2-positive (non-luminal) and triple-negative, is important for treatment decision making (2). Interactions between cancer cells and the tumor microenvironment, composed of many types of cells including cancer-associated fibroblasts (CAFs), endothelial cells, myofibroblasts and inflammatory cells, play an important role in cancer progression. Cells in the tumor microenvironment are immersed in a dynamic and functional extracellular matrix (ECMs) that mainly consists of collagen, proteoglycans (PGs), laminin, protease and fibronectin. PGs are major components of ECMs, and their expression is markedly modified in the tumor microenvironment (3). Serglycin (SRGN) is the only characterized member of intracellular PGs present in intracellular secretory vesicles and storage granules, and is highly expressed in hematopoietic cells (3, 4). It has been reported that SRGN is expressed by several types of carcinomas, including breast (5-7), liver (8), nasopharynx (9), colorectal (10) cancers, and promotes an aggressive phenotype. Overexpression of SRGN was reported to be an independent unfavorable prognostic factor for overall survival and relapse-free survival in hepatocellular carcinoma patients (8), and metastasis-free survival and disease-free survival in nasopharyngeal carcinoma patients (9). To our knowledge, only two studies have investigated SRGN expression in human breast cancer tissue samples by immunohistochemical analysis; however, the prognostic impact of SRGN expression has not been reported to date. This study is the first to report the prognostic impact of SRGN expression in breast cancer patients using immunohistochemistry. This study revealed unexpected findings, considering the tumor promoting function of SRGN, that low SRGN expression was an independent poor prognostic indicator in node-positive breast cancer patients.

Patients and Methods

Patients and tumor specimens. From January 2008 to December 2015, 493 consecutive female patients underwent surgical resection of breast cancer diagnosed as invasive carcinoma of no special type according to the World Health Organization classification of breast cancer (2) at Tottori University Hospital (Yonago, Japan). Out of which, 145 cases were excluded due to history of neoadjuvant treatment (70 cases), bilateral breast cancer (31 cases), distant metastasis (11 cases), unavailable tumor specimen (17 cases), microinvasive carcinoma (14 cases) and short follow-up time (2 cases). Thus, 348 patients were included in this analysis. Clinicopathological data of patients were obtained from the hospital medical records. The histopathological parameters including lymph node metastasis, Ki67 labeling index, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) statuses, were retrieved from the pathology reports. Histological grade was determined according to the Elston– Ellis’s criteria (11). ER-positive or PgR-positive was defined as ≥1% immunoreactive cells. HER2-positive was determined based on the Hercep Test (Dako Agilent Technology, CA, US) scored 3+. Cases that scored 2+ were considered as HER2-positive when the presence of HER2 amplification was detected through fluorescent in situ hybridization analysis using PathVysion kit (Abott-Vysis, Inc., Downers Grove, IL, USA). Written informed consent was obtained and this study was approved by the ethics committee of the Faculty of Medicine, Tottori University (approval number: 20A153; December 23, 2020).

Immunohistochemistry. All specimens were fixed in 10% neutrally buffered formalin and embedded in paraffin. The sections (4 µm-thick) were deparaffinized and endogenous peroxidase activity was blocked. Then, they were pre-treated in Tris-EDTA buffer (0.01 M, pH 9.0) using an autoclave (HICLAVE HG-50; HIRAYAMA Manufacturing Corp., Saitama, Japan) at 121°C for 10 min. After cooling to room temperature, nonspecific binding was blocked using a blocking buffer (BLOCK ACE; Megmilk Snow Brand, Sapporo, Japan). The sections were incubated at 4°C overnight with a monoclonal antibody against SRGN (clone HPA000759, diluted 1:1,000; SIGMA, Stockholm, Sweden). Subsequently, the sections were incubated using EnVision+ System HRP (DaKo). Finally, the slides were incubated with diaminobenzidine (DAB) solution (liquid DAB+ substrate and imidazole-HCI buffer, pH 7.5, containing hydrogen peroxide; Dako) for 5 min, and counterstained with hematoxylin.

Evaluation of the immunohistochemical findings. Cytoplasmic staining was considered as positive cells for SRGN. Normal breast epithelium and vascular endothelial cells served as the internal positive controls. The SRGN expression status was evaluated according to the methods described by Allread (12). Briefly, the intensity (0, negative; 1, weak; 2, moderate; 3, strong) and the proportion of positive cells (0, negative; 1, <1%; 2, 1-10%; 3, 11-33; 4, 34-66%; 5, ≥67%) were added, and cases were divided into two groups according to their scores as follows: low expression (scores, 0-4) and high expression (scores, 5-8). All slides were evaluated by K.H. and K.N. independently who were blinded to the patients’ clinicopathological data. The discordant cases were judged by Y.U.

Statistical analysis. All statistical analyses were performed using the SPSS version 25 software (IBM SPSS Statistics; IBM Corporation, Armonk, NY, USA). The association between SRGN expression status and clinicopathological factors was evaluated using non-parametric tests. The chi-square test and Fisher’s exact tests were used when there were two categorical variables of interest. The Kruskal–Wallis test was used when there were three or four variables. The Welch’s t-test was used for group-wise comparisons. For survival analysis, two different endpoints, cancer relapse (distant metastatic recurrence) and cancer-related death were used to calculate distant metastasis-free survival (DMFS) and disease-specific survival (DSS), respectively. DMFS was defined as the period from the date of initial surgery to the date of clinical or pathological cancer relapse with distant metastasis. DSS was defined as the period from the date of initial surgery to the date of cancer-related death. While calculating DMFS and DSS, patients were censored at the time of their last cancer-free follow-up or at the time of death due to a reason unrelated to breast cancer. Survival curves were computed based on the Kaplan-Meier methods, and differences in DMFS and DSS were tested using the log-rank test. The Cox proportional hazard regression model was used to perform univariate and multivariate analyses of several factors associated with DMFS and DSS. All tests were two-sided, and p-values <0.05 were considered statistically significant in all tests.

Results

Immunohistochemistry. The representative staining pattern of SRGN expression in invasive carcinoma of no special type is shown in Figure 1A. The reactivity for SRGN was mainly cytoplasmic, occasionally associated with cell membrane. The normal mammary epithelium (Figure 1B) and vascular endothelium served as internal positive controls.

Figure 1.
Figure 1.

Representative immunohistochemical staining of serglycin in invasive breast carcinoma and normal breast. (A) The reactivity of serglycin in carcinoma cells was mainly cytoplasm (×400). (B) Normal mammary epithelium showed cytoplasmic staining (×400).

Clinicopathological characteristics and association with SRGN expression. The clinicopathological characteristics of 348 patients with invasive carcinoma of no special type are summarized in Table I. Mastectomy and breast-conserving surgery were performed in 118 patients (33.9%) and 230 patients (66.1%), respectively. Two hundred and thirty-one patients (66.4%) received radiation therapy. Low SRGN expression was observed in 80 specimens (23.0%) and significantly correlated with high histological grade (p=0.001) and negative ER (p=0.013) (Table II). The SRGN score of node-negative and node-positive breast cancer patients’ groups was 5.36±1.79 and 5.46±1.50, respectively. The SRGN score of triple-negative (TN) subtype (4.45±2.22) was significantly lower compared to luminal A-like subtype (5.62±1.64, p=0.011) and luminal B-like (HER2-positive) subtype (5.31±1.67, p=0.030) (Figure 2). There were no correlations between low SRGN expression and clinicopathological variables in node-positive or -negative breast cancer patients.

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Table I.

Clinicopathological characteristics of 348 invasive carcinomas of no special type.

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Table II.

Association between serglycin expression and clinicopathological characteristics of 348 invasive carcinomas of no special type.

Figure 2.
Figure 2.

Comparison of serglycin score in 348 invasive breast carcinomas categorized by 5 subtypes.

Survival analysis according to SRGN expression status. The median follow-up time was 92.3 months (range=4-162 months). Thirty-four patients (9.8%) experienced metastatic recurrence, 23 patients (6.6%) died of breast cancer progression and 20 patients (5.7%) died of other causes, such as other cancer death (9 cases), pneumonia (3 cases), cardiovascular disease (2 cases), cerebellar hemorrhages (2 cases) and others (4 cases). The survival curves of DMFS and DSS for node-positive breast cancer patients are shown in Figure 3. The log-rank test showed that node-positive breast cancer patients with low SRGN expression had significantly shorter DMFS (p=0.016) and DSS (p=0.037). In node-positive breast cancer patients, the 5-year DMFS rates for low SRGN and high SRGN groups were 60.6% [95% confidence interval (CI)=0.346-0.790] and 89.0% (95% CI=0.782-0.946), respectively, whereas the 5-year DSS rates were 83.3% (95% CI=0.568-0.943) and 92.3% (95% CI=0.825-0.967), respectively. There were no significant correlations between SRGN expression and prognosis in 348 breast cancer patients or 256 node-negative breast cancer patients (data not shown). Univariate analysis in node-positive breast cancer patients showed a significant correlation between shorter DMFS and low SRGN expression status (p=0.023), large pathological tumor size (p=0.024), high histological grade (p=0.015), and negative ER (p=0.036). According to multivariate analysis, low SRGN expression had a significant effect on DMFS [hazard ratio (HR)=3.926; p=0.017] in addition to large pathological tumor size (HR=4.097; p=0.028) (Table III). Univariate analysis in node-positive breast cancer patients showed a significant correlation between shorter DSS and low SRGN expression (p=0.047), negative ER (p=0.011) and high histological grade (p=0.044). Multivariate analysis showed that low SRGN expression had a significant adverse effect on DSS (HR=3.968; p=0.020) in addition to negative ER (HR=4.667; p=0.021) (Table IV).

Figure 3.
Figure 3.

Kaplan-Meier survival curves for distant metastasis-free survival (A) and disease-specific survival (B) in 92 node-positive breast cancer patients based on serglycin expression status.

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Table III.

Univariate and multivariate analysis of various prognostic factors on distant metastasis-free survival in 92 node-positive invasive carcinoma patients.

View this table:
Table IV.

Univariate and multivariate analysis of various prognostic factors on disease-specific survival in 92 node-positive invasive carcinoma patients.

Discussion

SRGN is a major intracellular PG of hematopoietic cells and immune cells, and it is secreted into ECMs by tumor cells, thereby, activating multiple signaling cascades that evoke angiogenesis, tumor growth, epithelial to mesenchymal transition (EMT), tumor cell stemness, resistant to chemotherapy and metastasis. It has been considered that SRGN promotes the inflammatory process in the tumor microenvironment, eventually enhancing tumor cell invasion and metastasis. SRGN directly interacts with CD44 and other not identified receptors including integrins, thereby evoking cell adhesion and signaling. SRGN also regulates the secretion of proteolytic enzymes, IL-8, TGFβ2, CCL2, VEGF and HGF, eventually creating a pro-angiogenic and pro-inflammatory tumor microenvironment (4).

In breast cancer, few studies reported that SRGN promoted aggressive phenotype, and conferred invasion and metastasis in breast cancer cells in vitro (5-7). Only two reports (5, 6) investigated SRGN expression in human breast cancer tissues by immunohistochemical methods. Korpetinou et al. (5) firstly reported that SRGN expression was ubiquitously observed in eight breast carcinoma tissues and two normal breast tissues using immunohistochemistry, and that reactivity for SRGN was mainly observed in the cytoplasm, occasionally associated with the cell membrane. Our results of immunoreactivity for SRGN were in accordance with previous reports. SRGN protein expression in 106 TN breast cancer tissue was significantly higher than in 320 non-TN breast cancer tissues, and high score of SRGN staining was noted in node-positive breast cancer tissue compared with node-negative breast cancer tissue (6). In contrast, we revealed that the SRGN score of TN subtype was significantly lower compared to luminal A-like subtype or luminal B-like (HER2-positive) subtypes. These discrepancies may be mainly due to the differences in antibody used, immunohistochemical methods, SRGN scoring procedure, and cohort size. We used Allread scoring, which has been widely used for semi-quantitative scoring of ER expression in breast cancer and is familiar with pathologists. To investigate the impact of differences in scoring methods on our conclusion, we re-evaluated SRGN expression using the scoring methods described by Li et al. (9). Consequently, the conclusion that low SRGN was an independent poor prognostic indicator for node-positive breast cancer patients did not change (data not shown). To our knowledge, this is the first study to report the prognostic value of SRGN expression in breast cancer patients by immunohistochemistry. Contrasting the estimates from many previous reports that overexpression of SRGN promoted an aggressive phenotype, we revealed that low SRGN expression was an independent unfavorable prognostic factor in node-positive breast cancer patients. It has been considered over the years that SRGN plays an important role in the maintenance of inflammatory and proteolytic potential of tumor cells; therefore, many researchers have highlighted that SRGN promotes the aggressive phenotype of tumor cells and plays an essential role in progression such as invasion, metastasis and dissemination. In turn, it was reported that SRGN may act as a factor that can suppress spontaneous tumor expansion, and that the absence of SRGN enhanced the tumor vessel functionality by decreasing vascular endothelial growth factor and hepatocyte growth factor (13). As SRGN is also synthesized by inflammatory cells and CAFs, and secreted either constitutively or in a regulated manner, it plays a crucial role in the secretion of inflammatory mediator by these cells (14). Further studies evaluating SRGN expression in not only tumor cells but inflammatory cells and CAFs may be necessary for assessing its prognostic value. The conclusion that the low SRGN expression was an independent poor prognostic factor in node-positive breast cancer patients is preliminary because the number of patients was small and SRGN expression in inflammatory cells and CAFs was not evaluated. However, further investigation of SRGN expression using a large number of clinical samples may be helpful to clarify the very complex and divergent functions of SRGN in human breast cancer.

In conclusion, this is the first study to demonstrate that low SRGN expression is an independent poor prognostic factor in node-positive breast cancer patients. Although further studies with a larger number of cohorts are necessary, our findings suggest that immunohistochemical detection of SRGN expression could be useful in predicting aggressive phenotypes in node-positive breast cancer patients.

Acknowledgements

The Authors are grateful to Kazuko Fukushima and Yuko Urakami for their excellent technical assistance with the processing of the pathological specimens.

Footnotes

  • Authors’ Contributions

    Conception and design: K.H., K.N. and Y.U.; acquisition of data: K.H., M.W. and Y.S.; analysis and interpretation of data: K.H., K.N., Y.O., T.S. and Y.U.; writing, review, and/or revision of the manuscript: K.H., K.N., H.N. and Y.U. All Authors read and approved the final version.

  • ↵* These Authors contributed equally to this study.

  • Conflicts of Interest

    The Authors declare that there are no conflicts of interest regarding this study.

  • Received October 21, 2021.
  • Revision received November 9, 2021.
  • Accepted November 23, 2021.

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Clinical Significance of Serglycin Expression in Human Breast Cancer Patients
KEIKO HOSOYA, KANAE NOSAKA, TOMOHIKO SAKABE, MAKOTO WAKAHARA, YUKI OSHIMA, YOSHIMASA SUZUKI, HIROSHIGE NAKAMURA, YOSHIHISA UMEKITA
Anticancer Research Jan 2022, 42 (1) 279-285; DOI: 10.21873/anticanres.15483
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