Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype
Abstract
We demonstrate that glutathione biosynthesis is controlled by hypoxia-inducible factor 1 and is critical for chemotherapy-induced enrichment of breast cancer stem cells, making it an attractive therapeutic target in triple-negative breast cancer, which is the only subset of breast cancers for which there is no available targeted therapy. We also delineate a molecular mechanism in which glutathione functions as a signaling molecule to activate the breast cancer stem cell phenotype, establishing cross-talk between cancer metabolism and signal transduction. We also demonstrate that mitogen-activated protein kinase kinase (MEK)-ERK inhibitors and copper chelators have the countertherapeutic effect of inducing breast cancer stem cell enrichment.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 30, 2015
- Source ID
- 10.1073/pnas.1513433112
Entities
People
- Debangshu Samanta
- Gregg L. Semenza
- Haiquan Lu
- Hongxia Hu
- Huimin Zhang
- Ivan Chen
- John W. Bullen
- Lisha Xiang
Organizations
- American Cancer Society
- Congressionally Directed Medical Research Programs
- Johns Hopkins University