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Cell Death Differ. 2018 Feb;25(2):330-339. doi: 10.1038/cdd.2017.162. Epub 2017 Oct 13.

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

Wang D1,2,3,4, Xu J1,2,3,4, Liu B1,2,3,4, He X2, Zhou L1,2,3,4, Hu X2, Qiao F2, Zhang A5, Xu X6, Zhang H1,3, Wicha MS7, Zhang L2, Shao ZM2,8, Liu S2,3,4,9.

Author information

Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Science, University of Science & Technology of China, Hefei, Anhui, China.
Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
The CAS Key Laboratory of Innate Immunity and Chronic Disease, University of Science & Technology of China, Hefei, Anhui 230027, China.
Department of Pathology, Anhui Provincial Hospital, Southern District, Hefei, Anhui, China.
The Department of Breast Surgery, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Institutes of Biomedical Sciences, Fudan University, Shanghai, China.


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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