Clinical Significance of Receptor-Interacting Protein 3 and Parkin, Essential Molecules for Necroptosis, in Breast Cancer

Abstract

Purpose Receptor-interacting protein 3 (RIP3) is the main initiator of necroptosis. Parkin prevents the formation of the RIP1–RIP3 complex by promoting polyubiquitination of RIP3. However, the mechanism by which necroptosis affects the clinical features of breast cancer and prognosis is not known. Here, we aimed to study the effect of necroptosis on the clinical features and prognosis of breast cancer by assessing the expression of RIP3 and Parkin. Methods Tissue microarrays (TMAs) were constructed from 257 cases of breast cancer. Immunohistochemistry was performed on 4-μm tissue sections from each TMA block. The χ 2 test, Kaplan-Meier survival analysis with log-rank test, and Cox regression proportional hazard model were used for statistical analysis. Results Low RIP3 expression resulted in a large tumor size and high nuclear grade. Low RIP3 expression was correlated with human epidermal growth factor receptor 2 positivity, short overall survival (OS), and short disease-free survival (DFS). The triple negative breast cancer group with low RIP3 expression and lymph node (LN) positive group with low RIP3 expression had the shortest OS. High Parkin expression was associated with high histological grade, estrogen and/or progesterone receptor negativity, and lymphatic emboli, but was not correlated with OS and DFS. OS was correlated with LN metastasis and RIP3 loss and DFS with large tumor size, LN metastasis, and RIP3 loss. Conclusion Low RIP3 and high Parkin expression are associated with aggressive clinical features in breast cancer. RIP3, a molecular marker of necroptosis, is an independent factor associated with survival in breast cancer. Further in-depth studies are needed to investigate the role of necroptosis in breast cancer development, metastasis, and treatment in the future.

Role of Receptor Interacting Protein (RIP) kinases in cancer

“… 38 , 94 , 95 , 96 , 97 , 98 , 99 , 100 Low RIP3 expression was associated with worse clinical outcomes in metastatic CRC, malignant mesothelioma, and breast cancer patients. 99 , 101 , 102 RIP3 expression was also shown to be decreased during melanoma development. 103 Reconstituting RIP3 expression in RIP3 -silenced melanoma cells restored the ability of these cells to undergo necroptosis, suggesting a role of RIP3-mediated necroptosis in suppressing melanoma development.…”

The role of necroptosis in disease and treatment

“… 125 , 127 , 128 , 129 In addition to RIPK1, RIPK3 and MLKL are also involved in oncogenesis and related to prognosis. RIPK1/3 or MLKL is downregulated in breast cancer, 130 , 131 colorectal cancer, 132 , 133 , 134 melanoma, 135 gastric cancer, 136 ovarian cancer, 137 head and neck squamous cell carcinoma, 138 cervical squamous cell carcimoma, 139 and AML. 140 , 141 Since necroptosis can function as a tumor suppressor or a tumor promoter, the role of necroptosis in different types of malignant tumors remains to be further studied.…”

Necroptosis stimulates interferon-mediated protective anti-tumor immunity

“…RIPK3 expression is downregulated in many tumor types, suggesting that RIPK3 has important functions in tumor suppression [ 10 , 11 ]. In support of its anti-tumor role, lower RIPK3 expression correlates with worsened patient survival in lung cancer [ 12 ], chronic lymphocytic leukemia [ 13 ], colon cancer [ 14 ], malignant mesothelioma [ 15 ], and breast cancer [ 16 ]. In line with this, tumor RIPK3 expression appears to aid tumor immune surveillance.…”