Original Paper

IL6 blockade potentiates the anti-tumor effects of γ-secretase inhibitors in Notch3-expressing breast cancer

Received:
Revised:
Accepted:
Published online:

Edited by Y Shi

Abstract

Notch pathways have important roles in carcinogenesis including pathways involving the Notch1 and Notch2 oncogenes. Pan-Notch inhibitors, such as gamma secretase inhibitors (GSIs), have been used in the clinical trials, but the outcomes of these trials have been insufficient and have yielded unclear. In the present study, we demonstrated that GSIs, such as MK-0752 and RO4929097, inhibit breast tumor growth, but increase the breast cancer stem cell (BCSC) population in Notch3-expressing breast cancer cells, in a process that is coupled with IL6 induction and is blocked by the IL6R antagonist Tocilizumab (TCZ). IL6 induction results from inhibition of Notch3-Hey2 signaling through MK-0752. Furthermore, HIF1α upregulates Notch3 expression via direct binding to the Notch3 promoter and subsequently downregulates BCSCs by decreasing the IL6 levels in Notch3-expressing breast cancer cells. Utilizing both breast cancer cell line xenografts and patient-derived xenografts (PDX), we showed that the combination of MK-0752 and Tocilizumab significantly decreases BCSCs and inhibits tumor growth and thus might serve as a novel therapeutic strategy for treating women with Notch3-expressing breast cancers.

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Acknowledgements

Thanks to Dr Stephen Ethier for generously providing the breast cancer cell line SUM149. This work was supported by NSFC grant (81530075), the National Key Research and Development Program of China (Stem Cell and Translational Research 2016YFA0101202), the MOST grant (2015CB553800), NSFC grants (81472741 and 81322033), the CAS stem cell grant (XDA01040410), and the Fundamental Research Funds for the Central Universities (WK2070000034).

Author information

Author notes

    • Dong Wang
    •  & Jiahui Xu

    These authors contributed equally to this work

Affiliations

  1. Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Science, University of Science & Technology of China, Hefei, Anhui, China

    • Dong Wang
    • , Jiahui Xu
    • , Bingjie Liu
    • , Lei Zhou
    •  & Huafeng Zhang
  2. Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China

    • Dong Wang
    • , Jiahui Xu
    • , Bingjie Liu
    • , Xueyan He
    • , Lei Zhou
    • , Xin Hu
    • , Feng Qiao
    • , Lixing Zhang
    • , Zhi-ming Shao
    •  & Suling Liu
  3. Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China

    • Dong Wang
    • , Jiahui Xu
    • , Bingjie Liu
    • , Lei Zhou
    • , Huafeng Zhang
    •  & Suling Liu
  4. The CAS Key Laboratory of Innate Immunity and Chronic Disease, University of Science & Technology of China, Hefei, Anhui 230027, China

    • Dong Wang
    • , Jiahui Xu
    • , Bingjie Liu
    • , Lei Zhou
    •  & Suling Liu
  5. Department of Pathology, Anhui Provincial Hospital, Southern District, Hefei, Anhui, China

    • Anli Zhang
  6. The Department of Breast Surgery, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China

    • Xiaojun Xu
  7. University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

    • Max S Wicha
  8. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    • Zhi-ming Shao
  9. Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    • Suling Liu

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Competing interests

MSW has financial holdings and is a scientific advisor for OncoMed Pharmaceuticals, is a scientific advisor for Verastem, Paganini and MedImmune and receives research support from Dompe Pharmaceuticals and MedImmune. The remaining authors declare no conflict of interest.

Corresponding author

Correspondence to Suling Liu.

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