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DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway.

Authors :
Lin CC
Yang WH
Lin YT
Tang X
Chen PH
Ding CC
Qu DC
Alvarez JV
Chi JT
Source :
Oncogene [Oncogene] 2021 Mar; Vol. 40 (11), pp. 2018-2034. Date of Electronic Publication: 2021 Feb 18.
Publication Year :
2021

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.

Details

Language :
English
ISSN :
1476-5594
Volume :
40
Issue :
11
Database :
MEDLINE
Journal :
Oncogene
Publication Type :
Academic Journal
Accession number :
33603168
Full Text :
https://doi.org/10.1038/s41388-021-01676-x