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

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:

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.
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.

View this table:
Table I.

Patient characteristics.

View this table:
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.
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.

View this table:
Table III.

Analyses of the overall survival of patients with breast carcinoma.

View this table:
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.

References

  1. ↵
    1. Vandenabeele P,
    2. Galluzzi L,
    3. Vanden Berghe T and
    4. Kroemer G
    : Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11(10): 700-714, 2010. PMID: 20823910. DOI: 10.1038/nrm2970
    OpenUrlCrossRefPubMed
  2. ↵
    1. Liu Y,
    2. Liu T,
    3. Lei T,
    4. Zhang D,
    5. Du S,
    6. Girani L,
    7. Qi D,
    8. Lin C,
    9. Tong R and
    10. Wang Y
    : RIP1/RIP3-regulated necroptosis as a target for multifaceted disease therapy (Review). Int J Mol Med 44(3): 771-786, 2019. PMID: 31198981. DOI: 10.3892/ijmm.2019.4244
    OpenUrlCrossRefPubMed
  3. ↵
    1. Newton K
    : RIPK1 and RIPK3: critical regulators of inflammation and cell death. Trends Cell Biol 25(6): 347-353, 2015. PMID: 25662614. DOI: 10.1016/j.tcb.2015.01.001
    OpenUrlCrossRefPubMed
  4. ↵
    1. Kaiser WJ,
    2. Sridharan H,
    3. Huang C,
    4. Mandal P,
    5. Upton JW,
    6. Gough PJ,
    7. Sehon CA,
    8. Marquis RW,
    9. Bertin J and
    10. Mocarski ES
    : Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J Biol Chem 288(43): 31268-31279, 2013. PMID: 24019532. DOI: 10.1074/jbc.M113.462341
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Zhang Y,
    2. Su SS,
    3. Zhao S,
    4. Yang Z,
    5. Zhong CQ,
    6. Chen X,
    7. Cai Q,
    8. Yang ZH,
    9. Huang D,
    10. Wu R and
    11. Han J
    : RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nat Commun 8: 14329, 2017. PMID: 28176780. DOI: 10.1038/ncomms14329
    OpenUrlCrossRefPubMed
  6. ↵
    1. Orozco S,
    2. Yatim N,
    3. Werner MR,
    4. Tran H,
    5. Gunja SY,
    6. Tait SW,
    7. Albert ML,
    8. Green DR and
    9. Oberst A
    : RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis. Cell Death Differ 21(10): 1511-1521, 2014. PMID: 24902904. DOI: 10.1038/cdd.2014.76
    OpenUrlCrossRefPubMed
  7. ↵
    1. Kearney CJ,
    2. Cullen SP,
    3. Clancy D and
    4. Martin SJ
    : RIPK1 can function as an inhibitor rather than an initiator of RIPK3-dependent necroptosis. FEBS J 281(21): 4921-4934, 2014. PMID: 25195660. DOI: 10.1111/febs.13034
    OpenUrlCrossRefPubMed
  8. ↵
    1. Sun L,
    2. Wang H,
    3. Wang Z,
    4. He S,
    5. Chen S,
    6. Liao D,
    7. Wang L,
    8. Yan J,
    9. Liu W,
    10. Lei X and
    11. Wang X
    : Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148(1-2): 213-227, 2012. PMID: 22265413. DOI: 10.1016/j.cell.2011.11.031
    OpenUrlCrossRefPubMed
  9. ↵
    1. Feng X,
    2. Song Q,
    3. Yu A,
    4. Tang H,
    5. Peng Z and
    6. Wang X
    : Receptor-interacting protein kinase 3 is a predictor of survival and plays a tumor suppressive role in colorectal cancer. Neoplasma 62(4): 592-601, 2015. PMID: 25997957. DOI: 10.4149/neo_2015_071
    OpenUrlCrossRefPubMed
  10. ↵
    1. Koo GB,
    2. Morgan MJ,
    3. Lee DG,
    4. Kim WJ,
    5. Yoon JH,
    6. Koo JS,
    7. Kim SI,
    8. Kim SJ,
    9. Son MK,
    10. Hong SS,
    11. Levy JM,
    12. Pollyea DA,
    13. Jordan CT,
    14. Yan P,
    15. Frankhouser D,
    16. Nicolet D,
    17. Maharry K,
    18. Marcucci G,
    19. Choi KS,
    20. Cho H,
    21. Thorburn A and
    22. Kim YS
    : Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res 25(6): 707-725, 2015. PMID: 25952668. DOI: 10.1038/cr.2015.56
    OpenUrlCrossRefPubMed
  11. ↵
    1. Chung JH,
    2. Yoon SH,
    3. Kang YJ,
    4. Kim YS,
    5. Son BS,
    6. Kwon RJ,
    7. Han JH and
    8. Kim DH
    : Receptor-interacting protein kinase 3 as a predictive adjuvant chemotherapy marker after lung adenocarcinoma resection. Ann Transl Med 7(3): 42, 2019. PMID: 30906746. DOI: 10.21037/atm.2018.12.65
    OpenUrlCrossRefPubMed
  12. ↵
    1. Sun Y,
    2. Zhai L,
    3. Ma S,
    4. Zhang C,
    5. Zhao L,
    6. Li N,
    7. Xu Y,
    8. Zhang T,
    9. Guo Z,
    10. Zhang H,
    11. Xu P and
    12. Zhao X
    : Down-regulation of RIP3 potentiates cisplatin chemoresistance by triggering HSP90-ERK pathway mediated DNA repair in esophageal squamous cell carcinoma. Cancer Lett 418: 97-108, 2018. PMID: 29331417. DOI: 10.1016/j.canlet.2018.01.022
    OpenUrlCrossRefPubMed
  13. ↵
    1. Ruan J,
    2. Mei L,
    3. Zhu Q,
    4. Shi G and
    5. Wang H
    : Mixed lineage kinase domain-like protein is a prognostic biomarker for cervical squamous cell cancer. Int J Clin Exp Pathol 8(11): 15035-15038, 2015. PMID: 26823841.
    OpenUrlPubMed
  14. ↵
    1. Won KY,
    2. Min SY,
    3. Song JY,
    4. Lim SJ and
    5. Han SA
    : Clinical significance of receptor-interacting protein 3 and Parkin, essential molecules for necroptosis, in breast cancer. J Breast Cancer 24(1): 34-48, 2021. PMID: 33634619. DOI: 10.4048/jbc.2021.24.e12
    OpenUrlCrossRefPubMed
  15. ↵
    1. Kim HS,
    2. DO SI,
    3. Kim DH and
    4. Apple S
    : Clinicopathological and prognostic significance of programmed death ligand 1 expression in Korean patients with triple-negative breast carcinoma. Anticancer Res 40(3): 1487-1494, 2020. PMID: 32132048. DOI: 10.21873/anticanres.14093
    OpenUrlAbstract/FREE Full Text
    1. Kim SW,
    2. Kim HS and
    3. Na K
    : Characterization of Paired Box 8 (PAX8)-expressing metastatic breast carcinoma. Anticancer Res 40(10): 5925-5932, 2020. PMID: 32988924. DOI: 10.21873/anticanres.14613
    OpenUrlAbstract/FREE Full Text
    1. Park S,
    2. Cho EY,
    3. Oh YL,
    4. Park YH and
    5. Kim HS
    : Primary peritoneal high-grade serous carcinoma misinterpreted as metastatic breast carcinoma: a rare encounter in peritoneal fluid cytology. Anticancer Res 40(5): 2933-2939, 2020. PMID: 32366445. DOI: 10.21873/anticanres.14271
    OpenUrlAbstract/FREE Full Text
    1. Woo HY,
    2. DO SI,
    3. Kim SH,
    4. Song SY and
    5. Kim HS
    : Promoter methylation down-regulates B-cell translocation gene 1 expression in breast carcinoma. Anticancer Res 39(10): 5361-5367, 2019. PMID: 31570430. DOI: 10.21873/anticanres.13729
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Na K,
    2. Lee JY,
    3. Sung JY,
    4. Kim GM,
    5. Koo JS and
    6. Kim HS
    : Comparative clinicopathological and cytomorphological analyses of peritoneal carcinomatosis associated with metastatic breast carcinoma and primary peritoneal/ovarian carcinoma in patients with a history of breast carcinoma. Virchows Arch 473(2): 165-175, 2018. PMID: 29926183. DOI: 10.1007/s00428-018-2390-5
    OpenUrlCrossRefPubMed
  20. ↵
    1. Do SI,
    2. Yoon G,
    3. Kim HS,
    4. Kim K,
    5. Lee H,
    6. Do IG,
    7. Kim DH,
    8. Chae SW and
    9. Sohn JH
    : Increased Brahma-related gene 1 expression predicts distant metastasis and shorter survival in patients with invasive ductal carcinoma of the breast. Anticancer Res 36(9): 4873-4882, 2016. PMID: 27630343. DOI: 10.21873/anticanres.11051
    OpenUrlAbstract/FREE Full Text
    1. Kim HS,
    2. Yoon G,
    3. Ryu JY,
    4. Cho YJ,
    5. Choi JJ,
    6. Lee YY,
    7. Kim TJ,
    8. Choi CH,
    9. Song SY,
    10. Kim BG,
    11. Bae DS and
    12. Lee JW
    : Sphingosine kinase 1 is a reliable prognostic factor and a novel therapeutic target for uterine cervical cancer. Oncotarget 6(29): 26746-26756, 2015. PMID: 26311741. DOI: 10.18632/oncotarget.4818
    OpenUrlCrossRefPubMed
    1. Kim EK,
    2. Yoon G and
    3. Kim HS
    : Chemotherapy-induced endometrial pathology: mimicry of malignancy and viral endometritis. Am J Transl Res 8(5): 2459-2467, 2016. PMID: 27347355.
    OpenUrlPubMed
    1. Yoon N,
    2. Kim JY and
    3. Kim HS
    : Clinical outcomes of advanced-stage glassy cell carcinoma of the uterine cervix: a need for reappraisal. Oncotarget 7(48): 78448-78454, 2016. PMID: 27793022. DOI: 10.18632/oncotarget.12905
    OpenUrlCrossRefPubMed
    1. Yoon G,
    2. Koh CW,
    3. Yoon N,
    4. Kim JY and
    5. Kim HS
    : Stromal p16 expression is significantly increased in endometrial carcinoma. Oncotarget 8(3): 4826-4836, 2017. PMID: 27902476. DOI: 10.18632/oncotarget.13594
    OpenUrlCrossRefPubMed
    1. Na K,
    2. Sung JY and
    3. Kim HS
    : Stromal p16 overexpression in adult granulosa cell tumors of the ovary. Anticancer Res 37(5): 2437-2444, 2017. PMID: 28476811. DOI: 10.21873/anticanres.11583
    OpenUrlAbstract/FREE Full Text
    1. Lee H,
    2. Kim H and
    3. Kim HS
    : Mesonephric adenocarcinoma of the vagina harboring TP53 mutation. Diagnostics (Basel) 12(1): 119, 2022. PMID: 35054285. DOI: 10.3390/diagnostics12010119
    OpenUrlCrossRefPubMed
    1. Lee J,
    2. Park S,
    3. Woo HY and
    4. Kim HS
    : Clinicopathological characteristics of microscopic tubal intraepithelial metastases from adenocarcinoma and small cell neuroendocrine carcinoma of the uterine cervix. In Vivo 35(4): 2469-2481, 2021. PMID: 34182533. DOI: 10.21873/invivo.12527
    OpenUrlAbstract/FREE Full Text
    1. Kwon HJ,
    2. Song SY and
    3. Kim HS
    : Prominent papillary growth pattern and severe nuclear pleomorphism induced by neoadjuvant chemotherapy in ovarian mucinous carcinoma: potential for misdiagnosis as high-grade serous carcinoma. Anticancer Res 41(3): 1579-1586, 2021. PMID: 33788752. DOI: 10.21873/anticanres.14918
    OpenUrlAbstract/FREE Full Text
    1. Koh HH,
    2. Jung YY and
    3. Kim HS
    : Clinicopathological characteristics of gastric-type endocervical adenocarcinoma misdiagnosed as an endometrial, ovarian or extragenital malignancy, or mistyped as usual-type endocervical adenocarcinoma. In Vivo 35(4): 2261-2273, 2021. PMID: 34182505. DOI: 10.21873/invivo.12499
    OpenUrlAbstract/FREE Full Text
    1. Kim H,
    2. Na K,
    3. Bae GE and
    4. Kim HS
    : Mesonephric-like adenocarcinoma of the uterine corpus: comprehensive immunohistochemical analyses using markers for mesonephric, endometrioid and serous tumors. Diagnostics (Basel) 11(11): 2042, 2021. PMID: 34829389. DOI: 10.3390/diagnostics11112042
    OpenUrlCrossRefPubMed
  31. ↵
    1. Na K and
    2. Kim HS
    : Clinicopathologic and molecular characteristics of mesonephric adenocarcinoma arising from the uterine body. Am J Surg Pathol 43(1): 12-25, 2019. PMID: 29189288. DOI: 10.1097/PAS.0000000000000991
    OpenUrlCrossRefPubMed
  32. ↵
    1. Harvey JM,
    2. Clark GM,
    3. Osborne CK and
    4. Allred DC
    : Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17(5): 1474-1481, 1999. PMID: 10334533. DOI: 10.1200/JCO.1999.17.5.1474
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Wolff AC,
    2. Hammond ME,
    3. Hicks DG,
    4. Dowsett M,
    5. McShane LM,
    6. Allison KH,
    7. Allred DC,
    8. Bartlett JM,
    9. Bilous M,
    10. Fitzgibbons P,
    11. Hanna W,
    12. Jenkins RB,
    13. Mangu PB,
    14. Paik S,
    15. Perez EA,
    16. Press MF,
    17. Spears PA,
    18. Vance GH,
    19. Viale G,
    20. Hayes DF, American Society of Clinical Oncology and College of American Pathologists
    : Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med 138(2): 241-256, 2014. PMID: 24099077. DOI: 10.5858/arpa.2013-0953-SA
    OpenUrlCrossRefPubMed
  34. ↵
    1. Shen F,
    2. Pan X,
    3. Li M,
    4. Chen Y,
    5. Jiang Y and
    6. He J
    : Pharmacological inhibition of necroptosis promotes human breast cancer cell proliferation and metastasis. Onco Targets Ther 13: 3165-3176, 2020. PMID: 32368076. DOI: 10.2147/OTT.S246899
    OpenUrlCrossRefPubMed
  35. ↵
    1. Wu X,
    2. Wu MY,
    3. Jiang M,
    4. Zhi Q,
    5. Bian X,
    6. Xu MD,
    7. Gong FR,
    8. Hou J,
    9. Tao M,
    10. Shou LM,
    11. Duan W,
    12. Chen K,
    13. Shen M and
    14. Li W
    : TNF-α sensitizes chemotherapy and radiotherapy against breast cancer cells. Cancer Cell Int 17: 13, 2017. PMID: 28127258. DOI: 10.1186/s12935-017-0382-1
    OpenUrlCrossRefPubMed
  36. ↵
    1. Lu C,
    2. Zhou LY,
    3. Xu HJ,
    4. Chen XY,
    5. Tong ZS,
    6. Liu XD,
    7. Jia YS and
    8. Chen Y
    : RIP3 overexpression sensitizes human breast cancer cells to parthenolide in vitro via intracellular ROS accumulation. Acta Pharmacol Sin 35(7): 929-936, 2014. PMID: 24909514. DOI: 10.1038/aps.2014.31
    OpenUrlCrossRefPubMed
  37. ↵
    1. Ghorbani-Abdi-Saedabad A,
    2. Hanafi-Bojd MY,
    3. Parsamanesh N,
    4. Tayarani-Najaran Z,
    5. Mollaei H and
    6. Hoshyar R
    : Anticancer and apoptotic activities of parthenolide in combination with epirubicin in mda-mb-468 breast cancer cells. Mol Biol Rep 47(8): 5807-5815, 2020. PMID: 32686017. DOI: 10.1007/s11033-020-05649-3
    OpenUrlCrossRefPubMed
    1. Jin X,
    2. Lu X,
    3. Zhang Z and
    4. Lv H
    : Indocyanine green-parthenolide thermosensitive liposome combination treatment for triple-negative breast cancer. Int J Nanomedicine 15: 3193-3206, 2020. PMID: 32440118. DOI: 10.2147/IJN.S245289
    OpenUrlCrossRefPubMed
  39. ↵
    1. Araújo TG,
    2. Vecchi L,
    3. Lima PMAP,
    4. Ferreira EA,
    5. Campos IM,
    6. Brandão DC,
    7. Guimarães GS,
    8. Ribeiro MA and
    9. Filho AADS
    : Parthenolide and its analogues: a new potential strategy for the treatment of triple-negative breast tumors. Curr Med Chem 27(39): 6628-6642, 2020. PMID: 31419929. DOI: 10.2174/0929867326666190816230121
    OpenUrlCrossRefPubMed
  40. ↵
    1. Zhang L,
    2. Guo W,
    3. Yu J,
    4. Li C,
    5. Li M,
    6. Chai D,
    7. Wang W and
    8. Deng W
    : Receptor-interacting protein in malignant digestive neoplasms. J Cancer 12(14): 4362-4371, 2021. PMID: 34093836. DOI: 10.7150/jca.57076
    OpenUrlCrossRefPubMed
  41. ↵
    1. Zhu G,
    2. Ye J,
    3. Huang Y,
    4. Zheng W,
    5. Hua J,
    6. Yang S,
    7. Zhuang J and
    8. Wang J
    : Receptor-interacting protein-1 promotes the growth and invasion in gastric cancer. Int J Oncol 48(6): 2387-2398, 2016. PMID: 27035122. DOI: 10.3892/ijo.2016.3455
    OpenUrlCrossRefPubMed
  42. ↵
    1. Zhu G,
    2. Chen X,
    3. Wang X,
    4. Li X,
    5. Du Q,
    6. Hong H,
    7. Tang N,
    8. She F and
    9. Chen Y
    : Expression of the RIP-1 gene and its role in growth and invasion of human gallbladder carcinoma. Cell Physiol Biochem 34(4): 1152-1165, 2014. PMID: 25277242. DOI: 10.1159/000366328
    OpenUrlCrossRefPubMed
  43. ↵
    1. Seifert L,
    2. Werba G,
    3. Tiwari S,
    4. Giao Ly NN,
    5. Alothman S,
    6. Alqunaibit D,
    7. Avanzi A,
    8. Barilla R,
    9. Daley D,
    10. Greco SH,
    11. Torres-Hernandez A,
    12. Pergamo M,
    13. Ochi A,
    14. Zambirinis CP,
    15. Pansari M,
    16. Rendon M,
    17. Tippens D,
    18. Hundeyin M,
    19. Mani VR,
    20. Hajdu C,
    21. Engle D and
    22. Miller G
    : The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 532(7598): 245-249, 2016. PMID: 27049944. DOI: 10.1038/nature17403
    OpenUrlCrossRefPubMed
  44. ↵
    1. Qi ZH,
    2. Xu HX,
    3. Zhang SR,
    4. Xu JZ,
    5. Li S,
    6. Gao HL,
    7. Jin W,
    8. Wang WQ,
    9. Wu CT,
    10. Ni QX,
    11. Yu XJ and
    12. Liu L
    : RIPK4/PEBP1 axis promotes pancreatic cancer cell migration and invasion by activating RAF1/MEK/ERK signaling. Int J Oncol 52(4): 1105-1116, 2018. PMID: 29436617. DOI: 10.3892/ijo.2018.4269
    OpenUrlCrossRefPubMed
  45. ↵
    1. Liu ZY,
    2. Zheng M,
    3. Li YM,
    4. Fan XY,
    5. Wang JC,
    6. Li ZC,
    7. Yang HJ,
    8. Yu JM,
    9. Cui J,
    10. Jiang JL,
    11. Tang J and
    12. Chen ZN
    : RIP3 promotes colitis-associated colorectal cancer by controlling tumor cell proliferation and CXCL1-induced immune suppression. Theranostics 9(12): 3659-3673, 2019. PMID: 31281505. DOI: 10.7150/thno.32126
    OpenUrlCrossRefPubMed
    1. He GW,
    2. Günther C,
    3. Thonn V,
    4. Yu YQ,
    5. Martini E,
    6. Buchen B,
    7. Neurath MF,
    8. Stürzl M and
    9. Becker C
    : Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice. J Exp Med 214(6): 1655-1662, 2017. PMID: 28476895. DOI: 10.1084/jem.20160442
    OpenUrlAbstract/FREE Full Text
    1. Zeng F,
    2. Chen X,
    3. Cui W,
    4. Wen W,
    5. Lu F,
    6. Sun X,
    7. Ma D,
    8. Yuan Y,
    9. Li Z,
    10. Hou N,
    11. Zhao H,
    12. Bi X,
    13. Zhao J,
    14. Zhou J,
    15. Zhang Y,
    16. Xiao RP,
    17. Cai J and
    18. Zhang X
    : RIPK1 binds MCU to mediate induction of mitochondrial Ca2+ uptake and promotes colorectal oncogenesis. Cancer Res 78(11): 2876-2885, 2018. PMID: 29531160. DOI: 10.1158/0008-5472.CAN-17-3082
    OpenUrlAbstract/FREE Full Text
    1. Moriwaki K,
    2. Bertin J,
    3. Gough PJ,
    4. Orlowski GM and
    5. Chan FK
    : Differential roles of RIPK1 and RIPK3 in TNF-induced necroptosis and chemotherapeutic agent-induced cell death. Cell Death Dis 6: e1636, 2015. PMID: 25675296. DOI: 10.1038/cddis.2015.16
    OpenUrlCrossRefPubMed
    1. Bozec D,
    2. Iuga AC,
    3. Roda G,
    4. Dahan S and
    5. Yeretssian G
    : Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis. Oncotarget 7(29): 46384-46400, 2016. PMID: 27344176. DOI: 10.18632/oncotarget.10135
    OpenUrlCrossRefPubMed
    1. Wang C,
    2. Yao B,
    3. Xu M and
    4. Zheng X
    : RIP1 upregulation promoted tumor progression by activating AKT/Bcl-2/BAX signaling and predicted poor postsurgical prognosis in HCC. Tumour Biol 37(11): 15305-15313, 2016. PMID: 27699664. DOI: 10.1007/s13277-016-5342-1
    OpenUrlCrossRefPubMed
    1. Li YM,
    2. Liu ZY,
    3. Wang JC,
    4. Yu JM,
    5. Li ZC,
    6. Yang HJ,
    7. Tang J and
    8. Chen ZN
    : Receptor-interacting protein kinase 3 deficiency recruits myeloid-derived suppressor cells to hepatocellular carcinoma through the chemokine (C-X-C Motif) ligand 1-chemokine (C-X-C Motif) receptor 2 axis. Hepatology 70(5): 1564-1581, 2019. PMID: 31021443. DOI: 10.1002/hep.30676
    OpenUrlCrossRefPubMed
    1. Xu B,
    2. Xu M,
    3. Tian Y,
    4. Yu Q,
    5. Zhao Y,
    6. Chen X,
    7. Mi P,
    8. Cao H,
    9. Zhang B,
    10. Song G,
    11. Zhan YY and
    12. Hu T
    : Matrine induces RIP3-dependent necroptosis in cholangiocarcinoma cells. Cell Death Discov 3: 16096, 2017. PMID: 28179994. DOI: 10.1038/cddiscovery.2016.96
    OpenUrlCrossRefPubMed
  53. ↵
    1. Akara-Amornthum P,
    2. Lomphithak T,
    3. Choksi S,
    4. Tohtong R and
    5. Jitkaew S
    : Key necroptotic proteins are required for Smac mimetic-mediated sensitization of cholangiocarcinoma cells to TNF-α and chemotherapeutic gemcitabine-induced necroptosis. PLoS One 15(1): e0227454, 2020. PMID: 31914150. DOI: 10.1371/journal.pone.0227454
    OpenUrlCrossRefPubMed
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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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