IL1R2 Blockade Suppresses Breast Tumorigenesis and Progression by Impairing USP15‐Dependent BMI1 Stability

Advanced Science

Jing Feng¹  Ying Du¹  Xi‐chun Hu²  Jian Zhang²  Zhi‐ming Shao³  Lei Zhou³  Xin Hu³  Xiaoli Yang³  Dong Wang³  Xueyan He³  Dandan Sheng³  Yi‐zhou Jiang³  Suling Liu³  Lixing Zhang³  Jiankun Qiang³  Adeel ur Rehman⁴  Weilong Chen⁴  Tao Li⁵ 

[1] Department of Laboratory Medicine and Central Laboratory Southern Medical University Affiliated Fengxian Hospital Shanghai 201499 China;Department of Medical Oncology Shanghai Medical College Fudan University Shanghai 200032 China;Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences Shanghai Medical College Key Laboratory of Breast Cancer in Shanghai Innovation Center for Cell Signaling Network Cancer Institute Fudan University Shanghai 200032 China;School of Life Science The CAS Key Laboratory of Innate Immunity and Chronic Disease University of Science and Technology of China Hefei Anhui 230027 China;State Key Laboratory of Proteomics Institute of Basic Medical Sciences National Center of Biomedical Analysis Beijing 100850 China;

关键词: BMI1;    breast cancer;    IL1R2;    neutralizing antibody;    tumor initiating cells;    USP15;   

DOI  :  10.1002/advs.201901728

来源: DOAJ

【 摘 要 】

Abstract Breast tumor initiating cells (BTICs) with ALDH+CD24−CD44+ phenotype are the most tumorigenic and invasive cell population in breast cancer. However, the molecular mechanisms are still unclear. Here, it is found that a negative immune regulator interleukin‐1 receptor type 2 (IL1R2) is upregulated in breast cancer (BC) tissues and especially in BTICs. BC patients with high IL1R2 expression have a poorer overall survival and relapse‐free survival. High IL1R2 promotes BTIC self‐renewal and BC cell proliferation and invasion. Mechanistically, IL1R2 is activated by IL1β, as demonstrated by the fact that IL1β induces the release of IL1R2 intracellular domain (icd‐IL1R2) and icd‐IL1R2 then interacts with the deubiquitinase USP15 at the UBL2 domain and promotes its activity, which finally induces BMI1 deubiquitination at lysine 81 and stabilizes BMI1 protein. In addition, IL1R2 neutralizing antibody can suppress the protein expression of both IL1R2 and BMI1, and significantly abrogates the promoting effect of IL1R2 on BTIC self‐renewal and BC cell growth both in vitro and in vivo. The current results indicate that blocking IL1R2 with neutralizing antibody provides a therapeutic approach to inhibit BC progression by targeting BTICs.

【 授权许可】

Unknown