期刊
GENES & DEVELOPMENT
卷 29, 期 15, 页码 1631-1648出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.262642.115
关键词
genetic screen; HER2; STAT3; tailored therapies; breast cancer
资金
- National Institutes of Health [R01/EUREKA R01CA153233]
- American Association for Cancer Research-Stand up to Cancer award
- National Cancer Center
- NATIONAL CANCER INSTITUTE [R01CA153233] Funding Source: NIH RePORTER
HER2-positive (HER2(+)) breast adenocarcinomas are a heterogeneous group in which hormone receptor (HR) status influences therapeutic decisions and patient outcome. By combining genome-wide RNAi screens with regulatory network analysis, we identified STAT3 as a critically activated master regulator of HR-/HER2(+) tumors, eliciting tumor dependency in these cells. Mechanistically, HR-/HER2(+) cells secrete high levels of the interleukin-6 (IL-6) cytokine, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion. Increased calprotectin levels activate signaling pathways involved in proliferation and resistance. Importantly, we demonstrated that inhibition of the IL-6-Janus kinase 2 (JAK2)-STAT3-calprotectin axis with FDA-approved drugs, alone and in combination with HER2 inhibitors, reduced the tumorigenicity of HR-/HER2(+) breast cancers, opening novel targeted therapeutic opportunities.
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