DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway
- 18 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (11), 2018-2034
- https://doi.org/10.1038/s41388-021-01676-x
Abstract
Recurrent breast cancer presents significant challenges with aggressive phenotypes and treatment resistance. Therefore, novel therapeutics are urgently needed. Here, we report that murine recurrent breast tumor cells, when compared with primary tumor cells, are highly sensitive to ferroptosis. Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), the receptor for collagen I, is highly expressed in ferroptosis-sensitive recurrent tumor cells and human mesenchymal breast cancer cells. EMT regulators, TWIST and SNAIL, significantly induce DDR2 expression and sensitize ferroptosis in a DDR2-dependent manner. Erastin treatment induces DDR2 upregulation and phosphorylation, independent of collagen I. Furthermore, DDR2 knockdown in recurrent tumor cells reduces clonogenic proliferation. Importantly, both the ferroptosis protection and reduced clonogenic growth may be compatible with the compromised YAP/TAZ upon DDR2 inhibition. Collectively, these findings identify the important role of EMT-driven DDR2 upregulation in recurrent tumors in maintaining growth advantage but activating YAP/TAZ-mediated ferroptosis susceptibility, providing potential strategies to eradicate recurrent breast cancer cells with mesenchymal features.Keywords
Funding Information
- U.S. Department of Defense (W81XWH-15-1-0486, W81XWH-17-1-0143)
- U.S. Department of Health & Human Services | National Institutes of Health (1R01NS111588-01A1, R01GM124062)
- U.S. Department of Health & Human Services | National Institutes of Health
This publication has 73 references indexed in Scilit:
- The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasisNature, 2013
- Comprehensive molecular portraits of human breast tumoursNature, 2012
- Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell DeathCell, 2012
- The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroupsNature, 2012
- Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway–dependent and PI3K pathway–independent mechanismsNature Medicine, 2011
- Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung CancerCancer Discovery, 2011
- Discoidin domain receptor 2 is a critical regulator of epithelial–mesenchymal transitionMatrix Biology, 2011
- miRNA-mRNA Integrated Analysis Reveals Roles for miRNAs in Primary Breast TumorsPLOS ONE, 2011
- Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancerBreast Cancer Research, 2010
- The basics of epithelial-mesenchymal transitionJCI Insight, 2009