2. Academic Validation
  3. Macrophages confer resistance to BET inhibition in triple-negative breast cancer by upregulating IKBKE

Macrophages confer resistance to BET inhibition in triple-negative breast cancer by upregulating IKBKE

  • Biochem Pharmacol. 2020 Oct;180:114126. doi: 10.1016/j.bcp.2020.114126.
Jianghua Qiao 1,  Yibing Chen 2,  Yanjun Mi 3,  Huan Jin 4,  Lina Wang 1,  Ting Huang 4,  Haolong Li 4,  Yucen Song 2,  Jun Cao 2,  Baoyan Wu 4,  Qiming Wang 5,  Zhengzhi Zou 6
Affiliations

Affiliations

  • 1 Department of Breast Disease, Henan Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital. Zhengzhou 450008 China.
  • 2 Genetic and Prenatal Diagnosis Center, Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China.
  • 3 Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research and Thoracic Tumor Diagnosis & Treatment, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen 361003, China.
  • 4 MOE Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
  • 5 Department of Clinical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital. Zhengzhou 450008, China. Electronic address: qimingwang1006@126.com.
  • 6 MOE Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China. Electronic address: zouzhengzhi@m.scnu.edu.cn.
PMID: 32603665 DOI: 10.1016/j.bcp.2020.114126
Abstract

BET inhibitors (BETi) exhibit a strong anti-tumor activity in triple-negative breast Cancer (TNBC). However, BETi resistance has been reported in TNBC. The mechanisms of resistance have not been demonstrated. Tumor-associated macrophages (TAMs) are frequently involved in Cancer cells resistance to chemotherapy, also associated with poor prognosis in TNBC. However, the role of TAMs in BETi resistance remains unknown. Here, we found that BETi JQ1 and I-BET151 exerted anti-tumor effects in TNBC by decreasing IKBKE expression to attenuate NF-κB signaling. TAMs have been reported to associate with chemoresistance in breast Cancer. Here, we firstly found that TNBC-stimulated TAMs activated NF-κB signaling by upregulating IKBKE expression to enhance breast Cancer cells resistance to BETi. The IKBKE levels were also proved to be higher in clinical TNBC tissues than Non-TNBC tissues, suggesting feedback induction of IKBKE expression by TNBC-stimulated TAMs in TNBC. Moreover, the induction of IKBKE by TAMs in TNBC cells was identified to be associated with STAT3 signaling, which was activated by TAM-secreted IL-6 and IL-10. Lastly, the combination of inhibitors of BET and STAT3 exerted a synergistic inhibition effects in TAM-cocultured or TAM CM-treated TNBC cells in vitro and in vivo. Altogether, our findings illustrated TNBC-activated macrophages conferred TNBC cells resistance to BETi via IL-6 or IL-10/STAT3/IKBKE/NF-κB axis. Blockade of IKBKE or double inhibition of BET and STAT3 might be a novel strategy for treatment of TNBC.

Keywords

BET inhibition; IKBKE; Macrophages; STAT3; Triple-negative breast cancer.

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