Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer

Tan, Yiqing; Sun, Ran; Liu, Lei; Yang, Dejuan; Xiang, Qin; Li, Li; Tang, Jun; Qiu, Zhu; Peng, Weiyan; Wang, Yuanyuan; Ye, Lin; Ren, Guosheng; Xiang, Tingxiu

doi:10.7150/thno.58322

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Nanotheranostics 2024; 8(4): 442-457. [Abstract] [Full text] [PDF]

Nanotheranostics 2024; 8(4): 427-441. [Abstract] [Full text] [PDF]

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International Journal of Biological Sciences

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Theranostics 2021; 11(11):5214-5231. doi:10.7150/thno.58322 This issue Cite

Research Paper

Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer

Yiqing Tan^1,2, Ran Sun^1,3, Lei Liu¹, Dejuan Yang², Qin Xiang¹, Li Li¹, Jun Tang¹, Zhu Qiu¹, Weiyan Peng¹, Yuanyuan Wang², Lin Ye¹, Guosheng Ren^1✉, Tingxiu Xiang^1✉

1. Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
2. Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
3. Chongqing Jiulongpo People's Hospital, Chongqing 400024, China.

Citation:

Tan Y, Sun R, Liu L, Yang D, Xiang Q, Li L, Tang J, Qiu Z, Peng W, Wang Y, Ye L, Ren G, Xiang T. Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer. Theranostics 2021; 11(11):5214-5231. doi:10.7150/thno.58322. https://www.thno.org/v11p5214.htm

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Abstract

Rationale: Breast cancer (BrCa) is the most common cancer worldwide, and the 5-year relative survival rate has declined in patients diagnosed at stage IV. Advanced BrCa is considered as incurable, which still lack effective treatment strategies. Identifying and characterizing new tumor suppression genes is important to establish effective prognostic biomarkers or therapeutic targets for late-stage BrCa.

Methods: RNA-seq was applied in BrCa tissues and normal breast tissues. Through analyzing differentially expressed genes, DRD2 was selected for further analysis. And expression and promoter methylation status of DRD2 were also determined. DRD2 functions were analyzed by various cell biology assays in vitro. Subcutaneous tumor model was used to explore DRD2 effects in vivo. A co-cultivated system was constructed to investigate interactions of DRD2 and macrophages in vitro. WB, IHC, IF, TUNEL, qRT-PCR, Co-IP, Antibody Array, and Mass Spectrum analysis were further applied to determine the detailed mechanism.

Results: In BrCa, DRD2 was found to be downregulated due to promoter methylation. Higher expression of DRD2 positively correlated with longer survival times especially in HER2-positive patients. DRD2 also promoted BrCa cells sensitivity to Paclitaxel. Ectopic expression of DRD2 significantly inhibited BrCa tumorigenesis. DRD2 also induced apoptosis as well as necroptosis in vitro and in vivo. DRD2 restricted NF-κB signaling pathway activation through interacting with β-arrestin2, DDX5 and eEF1A2. Interestingly, DRD2 also regulated microenvironment as it facilitated M1 polarization of macrophages, and triggered GSDME-executed pyroptosis.

Conclusion: Collectively, this study novelly manifests the role of DRD2 in suppressing BrCa tumorigenesis, predicting prognosis and treatment response. And this study further reveals the critical role of DRD2 in educating M1 macrophages, restricting NF-κB signaling pathway and triggering different processes of programmed cell death in BrCa. Taking together, those findings represent a predictive and therapeutic target for BrCa.

Keywords: DRD2, Breast Cancer, Tumor Suppressor Genes, Macrophages, Pyroptosis.

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APA

Tan, Y., Sun, R., Liu, L., Yang, D., Xiang, Q., Li, L., Tang, J., Qiu, Z., Peng, W., Wang, Y., Ye, L., Ren, G., Xiang, T. (2021). Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer. Theranostics, 11(11), 5214-5231. https://doi.org/10.7150/thno.58322.

ACS

Tan, Y.; Sun, R.; Liu, L.; Yang, D.; Xiang, Q.; Li, L.; Tang, J.; Qiu, Z.; Peng, W.; Wang, Y.; Ye, L.; Ren, G.; Xiang, T. Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer. Theranostics 2021, 11 (11), 5214-5231. DOI: 10.7150/thno.58322.

NLM

CSE

Tan Y, Sun R, Liu L, Yang D, Xiang Q, Li L, Tang J, Qiu Z, Peng W, Wang Y, Ye L, Ren G, Xiang T. 2021. Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer. Theranostics. 11(11):5214-5231.

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