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Research ArticleClinical Studies

High Receptor-interacting Serine/Threonine-protein Kinase 3 (RIP3) Expression Serves as an Independent Poor Prognostic Factor for Triple-negative Breast Carcinoma

YUMIN CHUNG, SINAE KIM, HYUN-SOO KIM and SUNG-IM DO
Anticancer Research May 2022, 42 (5) 2753-2761; DOI: https://doi.org/10.21873/anticanres.15754
YUMIN CHUNG
1Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul, Republic of Korea;
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SINAE KIM
2Division of Biostatistics, Department of R&D Management, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;
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HYUN-SOO KIM
3Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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  • For correspondence: hyun-soo.kim@samsung.com sungim.do@samsung.com
SUNG-IM DO
1Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul, Republic of Korea;
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  • For correspondence: hyun-soo.kim@samsung.com sungim.do@samsung.com
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Abstract

Background/Aim: Receptor-interacting serine/threonine-protein kinase 3 (RIP3) is a key component related to tumor necrosis factor-dependent necroptosis. RIP3 has been known to be a predictive biomarker in many types of carcinomas. We aimed to investigate whether RIP3 expression is correlated with clinicopathological characteristics and the outcomes of patients with breast carcinoma. Patients and Methods: We performed immunostaining for RIP3 and analyzed the association of RIP3 expression status with the clinicopathological characteristics and survival of 203 patients with invasive ductal carcinoma of the breast. Results: High RIP3 expression was significantly correlated with lymph node metastasis and human epidermal growth factor receptor 2 positivity. In patients with triple-negative breast carcinoma (TNBC), high RIP3 expression was an independent prognostic factor for disease-free survival (DFS). RIP3-high TNBC showed the lowest DFS rate. Conclusion: High RIP3 expression is associated with aggressive clinical behavior of breast carcinoma. Our data suggest that RIP3 serves as an independent prognostic factor in TNBC.

Key Words:
  • Breast
  • receptor-interacting serine/threonine-protein kinase 3
  • immunohistochemistry
  • triple-negative breast carcinoma
  • prognosis

Receptor-interacting serine/threonine-protein kinase 3 (RIP3) is an essential factor involved in necrosis that occurs via a programmed pathway, which is also called necroptosis (1). Necroptosis is a type of cell death regulated by a specific signaling system, also known as the tumor necrosis factor (TNF) superfamily pathway (1, 2). This pathway is triggered by TNF and Toll-like receptors when pro-apoptotic caspase-8 is inhibited by pan-caspase inhibitors (3, 4). RIP1 and RIP3 are key kinase components that mediate the TNF-related signaling pathway (3). Once RIP1 is activated by autophosphorylation, it can phosphorylate downstream targets, including RIP3 (5). However, RIP1 does not always exert a positive effect on RIP3 (6). RIP1 can also inhibit RIP3-induced necroptosis (7), and furthermore, RIP3 alone can induce necroptosis independently of RIP1 (6). Taken together, data show that RIP3, but not RIP1, is essential for necroptosis. Additionally, Ser227, one of the phosphorylation sites of RIP3, is particularly important for the recruitment and activation of mixed-lineage kinase domain-like protein (MLKL). MLKL has recently been referred to as a key mediator of necroptosis signaling downstream of RIP3 (8). Previous studies have suggested that RIP3 serves as a potential biomarker for predicting chemotherapeutic response and patient outcome in different types of malignancies, such as colorectal carcinoma, pulmonary adenocarcinoma, esophageal squamous cell carcinoma (SCC), and breast cancer (9-12). Moreover, the expression of MLKL, a key downstream component of the RIP3-mediated signaling pathway, has been reported to be associated with the survival of patients with cervical SCC (13).

Some previous studies have reported RIP3 expression in breast carcinoma. Koo et al. (10) reported that RIP3 expression was reduced in breast carcinoma tissues compared with normal breast tissues due to genomic methylation. Another recent study by Won et al. (14) demonstrated that patients whose tumors displayed low RIP3 expression had a worse prognosis than those whose tumors had high RIP3 expression. However, whether the expression status of RIP3 has clinicopathological and prognostic significance in patients with breast carcinoma remains poorly understood. The purpose of this study was to investigate the immunohistochemical expression of RIP3 in breast carcinoma and to analyze its association with the clinicopathological characteristics and survival of patients with breast carcinoma.

Patients and Methods

Patient specimens. This study (2021-07-034-001) was approved by the Institutional Review Board of Kangbuk Samsung Hospital. We collected data on 203 consecutive cases of invasive ductal carcinoma (IDC) of the breast. The resected tissues were initially examined by pathologists before fixation in 10% neutral-buffered formalin. After fixation for 12−24 h, the tissues were thoroughly examined macroscopically and sectioned. After processing in an automatic tissue processor, the sections were paraffin-embedded, and 4-μm-thick sections were cut from each formalin-fixed, paraffin-embedded (FFPE) tissue block using a rotary microtome. Tissue slices were subsequently stained with hematoxylin and eosin (H&E) using an automatic staining instrument. Two board-certified pathologists examined all available slides by light microscopy. The following information was obtained from electronic medical records and pathology reports: patient age, modified Bloom-Richardson grade (15-19), pathological T (pT) and N (pN) stage, distant metastasis, stage, lymphovascular invasion, extensive intraductal component, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression status, triple-negative status, recurrence, death from IDC, and follow-up period. Histological grades were assigned based on the above-mentioned grading system.

Tissue microarray. Tissue microarray blocks were constructed as previously described (20). Briefly, all H&E-stained slides were reviewed thoroughly, and the two most representative tumor areas were marked on the corresponding FFPE tissue blocks. Two tissue cores, 2 mm in diameter, were obtained from each block and manually arrayed into recipient tissue microarray blocks. The assembly was held in an X-Y position guide, with a 1-mm increment between the individual cores, and the instrument was used to generate holes in a recipient block with defined array cores. The appropriate needle was used to transfer the cores into the recipient block. The percentage of tumor volume in each core was greater than 70%. A pair of tissue microarray blocks was made for each case.

Immunohistochemical staining. The 4-μm-thick FFPE sections were deparaffinized in xylene and then rehydrated in a graded series of alcohol solutions. Immunostaining was performed using an automatic immunostainer and a compact polymer method (Bond Intense Detection Kit, Leica Biosystems, Newcastle upon Tyne, UK), according to the manufacturer’s recommendations (20-31). The following primary antibodies were used: ER (1:200, clone SP1, Lab Vision Corporation, Fremont, CA, USA), PR (dilution 1:200, clone PgR 636, Dako, Glostrup, Denmark), HER2 (dilution 1:200, clone SP3, Lab Vision Corporation), and RIP3 (dilution 1:75, polyclonal, Invitrogen, San Diego, CA, USA). After chromogenic visualization (EnVision+ Detection Systems, Dako), sections were counterstained with hematoxylin and coverslipped. The ER and PR expression status was assessed using the Allred scoring method (32). HER2 expression status was evaluated according to the American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations (33). In cases with equivocal HER2 immunostaining (score 2+), silver-enhanced in situ hybridization (Ventana Medical Systems, Oro Valley, AZ, USA) was performed to determine whether the ERBB2 (erb-b2 receptor tyrosine kinase 2) gene was amplified. RIP3 expression was evaluated by estimating the staining intensity (0, absent; 1, weak; 2, moderate; and 3, strong). Two board-certified pathologists blinded to the clinicopathological information and patient identity examined the RIP3-immunostained slides and scored the staining intensity (Figure 1).

Figure 1.
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Figure 1.

Receptor-interacting serine/threonine-protein kinase 3 (RIP3) expression in breast carcinoma. Original magnification is indicated in the right lower corner of each image.

Statistical analysis. We used an independent two sample t-test, Pearson Chi-square test, Fisher exact test, or linear-by-linear association test to determine the association between RIP3 expression status and clinicopathological characteristics. Univariate and multivariate survival analyses were used to examine the prognostic significance of RIP3 expression. Kaplan–Meier curves were generated for overall survival (OS) and disease-free survival (DFS), and differences were analyzed by the log-rank test for univariate survival analysis. Multivariate survival analysis was performed using the Cox proportional hazards model (95% confidence interval) with a backward stepwise elimination method. Statistical analyses were performed using the R Package ‘stats’ Version 3.6.3. Statistical significance was defined as a p-value less than 0.05.

Results

Clinicopathological significance of RIP3 expression status. This study included 203 eligible patients with IDC of the breast who were diagnosed between January 2006 and December 2010. Table I summarizes their clinicopathological characteristics. An expression score cut-off value of 3, as calculated by the Kaplan–Meier curves, was used to dichotomize the patients into RIP3-high and RIP3-low groups. One hundred and twenty-eight IDCs (63.1%) were classified into the RIP3-low group, while the remaining 75 (36.9%) were classified into the RIP3-high group. Table II summarizes the associations of RIP3 expression status with the clinicopathological characteristics of IDC patients. More than half (45/75; 60.0%) of the patients whose tumors showed high RIP3 expression developed lymph node metastasis, whereas 43.0% (55/128) of patients in the RIP3-low group had nodal metastatic tumors. This difference was significant (p=0.019). The frequency of HER2 positivity (33.3%) in the RIP3-high group was significantly higher than that in the RIP3-low group (19.5%; p=0.028). No significant association was observed between RIP3 expression and age, stage, hormone receptor status, triple negativity, or extensive intraductal component.

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Table I.

Patient characteristics.

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Table II.

Clinicopathological significance of receptor-interacting serine/threonine-protein kinase 3 (RIP3) expression in breast carcinoma.

Prognostic significance of RIP3 expression status. Follow-up information was available for all 203 IDC patients. Among the patients, the difference in OS (p=0.620) and DFS (p=0.340) between RIP3-high and RIP3-low tumors was not significant (Figure 2). In the multivariate analyses, RIP3 was not an independent factor that affected OS (p=0.506; Table III) or DFS (p=0.191; Table IV).

Figure 2.
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Figure 2.

Kaplan–Meier plots for the overall survival (OS) and disease-free survival (DFS) of patients with breast carcinoma. No significant difference was observed in OS and DFS according to receptor-interacting serine/threonine-protein kinase 3 (RIP3) expression status in patients with invasive ductal carcinoma (IDC). In contrast, in patients with triple-negative breast carcinoma (TNBC), high RIP3 expression was a significant predictor of both OS and DFS.

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Table III.

Analyses of the overall survival of patients with breast carcinoma.

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Table IV.

Analyses of the disease-free survival of patients with breast carcinoma.

When the patients were subclassified according to triple-negative status, patients with RIP3-high TNBC had significantly worse OS (p=0.016) and DFS (p=0.009) than those with RIP3-low TNBC, RIP3-high non-TNBC, or RIP3-low non-TNBC (Figure 2). The RIP3-high TNBC group had the lowest OS and DFS. Multivariate analyses revealed that high RIP3 expression was an independent factor that affected DFS in patients with TNBC (Table IV).

Discussion

The expression profiles and predictive roles of RIP3 have been investigated in many different types of solid tumors. Feng et al. (9) reported the tumor-suppressive roles and prognostic significance of RIP3 in colorectal carcinoma. RIP3 expression in colorectal carcinoma was significantly lower than that in normal colorectal tissue and was shown to be an independent prognostic factor for both OS and DFS. Their in vitro study showed that RIP3 over-expression suppressed the growth of colorectal carcinoma cells. Sun et al. (12) showed that RIP3 expression was significantly down-regulated in esophageal SCC tissues, which led to cisplatin chemoresistance. They suggested that RIP3 regulates cisplatin sensitivity in esophageal SCC and is a potential marker that can predict chemosensitivity. Chung et al. (11) reported that high RIP3 expression was associated with prolonged DFS in patients with pulmonary adenocarcinoma who received postoperative cisplatin chemotherapy, which suggests that RIP3 over-expression is a potential biomarker that can identify patients with pulmonary adenocarcinoma who can benefit the most from cisplatin-based adjuvant chemotherapy. Several authors have documented the expression and prognostic implication of RIP3 in the breast. In a study by Koo et al. (10), the expression of both RIP3 protein and RIP3 mRNA was decreased in IDC, but the differences in the expression levels between molecular subtypes were not significant. Moreover, Won et al. (14) reported that low RIP3 expression was significantly correlated with HER2 positivity and worse survival. In an in vitro study by Shen et al. (34), pharmacological inhibition of the necroptosis signaling pathway by necrostatin-1 promoted the growth of breast cancer cells. Wu et al. (35) observed that TNF and 5-fluorouracil up-regulated and activated RIP3, which led to necroptosis in breast carcinoma cells and increased sensitivity to chemotherapy and radiotherapy. Similarly, Lu et al. (36) showed that RIP3 over-expression sensitized breast carcinoma cells to parthenolide, an anti-inflammatory agent that has been reported to inhibit carcinoma cell growth by inducing apoptosis (37-39).

In contrast, we demonstrated that high RIP3 expression in TNBC was significantly associated with poor OS and DFS and that RIP3 expression was an independent factor that could predict worse DFS in patients with TNBC. Our results are inconsistent with those of previous studies that indicated the tumor-suppressive role of RIP3 and the inverse relationship between RIP3 expression status and prognosis. Actually, the effects of RIP on tumorigenesis, biological behavior of tumors, and prognosis remain controversial. Zhang et al. (40) reported that the results were inconsistent among different gastrointestinal carcinomas or even within the same carcinoma type. For example, an increase in RIP1 expression in gastric and gallbladder carcinomas promoted tumorigenesis, which resulted in a poor prognosis (41, 42). Similarly, in another study, increased RIP1 and RIP3 expression promoted pancreatic carcinogenesis, and high RIP4 expression enhanced the migration and invasion of pancreatic carcinoma cells and predicted a poor outcome (43, 44). In patients with colorectal, hepatocellular, and cholangiocellular carcinoma, increased RIP3 expression was associated with either better or worse prognosis (9, 45-53). Therefore, it is difficult to state whether the role of RIP is pro-oncogenic or tumor-suppressive in malignant tumors. We considered the possibility that the biological consequences of the RIP signaling pathway are complicated due to its crosstalk with other signaling pathways. The possibility that the biological significance of RIP differs during tumor development according to cell or tissue type also cannot be excluded. To the best of our knowledge, this study is the first to demonstrate that RIP3 can be a poor prognostic factor in patients with TNBC. Since studies on the role of RIP3 in breast carcinoma are still scarce, we believe that additional data will either add further evidence of a pro-oncogenic role of RIP3 in breast carcinoma or will disprove our findings. Further investigations are warranted to clarify the molecular mechanism of RIP3 in mammary carcinogenesis.

In conclusion, we demonstrated that high RIP3 expression was significantly associated with lymph node metastasis and HER2 positivity. In the survival analyses, patients with TNBC whose tumors exhibited high RIP3 expression had significantly lower OS and DFS rates. RIP3 expression was an independent prognostic factor for worse DFS in patients with TNBC. Our observations were inconsistent with previously published data, and therefore, further investigations are needed to determine the relevance and prognostic implication of RIP3 in patients with breast carcinoma. We expect that additional data from larger cohorts of patients with TNBC will provide reliable information about the significance of RIP3 as it relates to clinicopathological factors and prognosis.

Acknowledgements

This research was supported by the Sungkyunkwan University and the BK21 FOUR (Graduate School Innovation) funded by the Ministry of Education (MOE, Korea) and National Research Foundation of Korea (NRF).

Footnotes

  • Authors’ Contributions

    All Authors made substantial contributions to the conceptualization and design of the study; the collection, analysis, and validation of the data; drafting of the article; critical revision of the article for important intellectual content; and the final approval of the version to be published.

  • Conflicts of Interest

    No Authors have any conflicts of interest or financial ties to declare regarding this study.

  • Received February 28, 2022.
  • Revision received March 14, 2022.
  • Accepted March 15, 2022.
  • Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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Anticancer Research: 42 (5)
Anticancer Research
Vol. 42, Issue 5
May 2022
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High Receptor-interacting Serine/Threonine-protein Kinase 3 (RIP3) Expression Serves as an Independent Poor Prognostic Factor for Triple-negative Breast Carcinoma
YUMIN CHUNG, SINAE KIM, HYUN-SOO KIM, SUNG-IM DO
Anticancer Research May 2022, 42 (5) 2753-2761; DOI: 10.21873/anticanres.15754

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High Receptor-interacting Serine/Threonine-protein Kinase 3 (RIP3) Expression Serves as an Independent Poor Prognostic Factor for Triple-negative Breast Carcinoma
YUMIN CHUNG, SINAE KIM, HYUN-SOO KIM, SUNG-IM DO
Anticancer Research May 2022, 42 (5) 2753-2761; DOI: 10.21873/anticanres.15754
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Keywords

  • Breast
  • receptor-interacting serine/threonine-protein kinase 3
  • immunohistochemistry
  • triple-negative breast carcinoma
  • prognosis
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