期刊
BRITISH JOURNAL OF CANCER
卷 125, 期 8, 页码 1146-1157出版社
SPRINGERNATURE
DOI: 10.1038/s41416-021-01510-x
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资金
- CDMRP/BCRP [BC095803]
- Howard Hughes Medical Institute Gilliam Predoctoral fellowship [PREDC 59008467]
- UPMC Hillman Cancer Center [P30-DK072506]
- Cotswold Foundation postdoctoral fellowship
- [R01 CA131350]
PRDX1 plays different roles in cancer progression, acting as a tumor suppressor in certain cell types while also being a potential drug target in cancer cell xenografts. The inactivation of PRDX1 in mammary fibroblasts promotes collagen remodelling and supports breast cancer progression. This study highlights the importance of PRDX1 protein levels in breast cancer cohorts for survival analysis.
Background Peroxiredoxin 1 (PRDX1) belongs to an abundant family of peroxidases whose role in cancer is still unresolved. While mouse knockout studies demonstrate a tumour suppressive role for PRDX1, in cancer cell xenografts, results denote PRDX1 as a drug target. Probably, this phenotypic discrepancy stems from distinct roles of PRDX1 in certain cell types or stages of tumour progression. Methods We demonstrate an important cell-autonomous function for PRDX1 utilising a syngeneic mouse model (BALB/c) and mammary fibroblasts (MFs) obtained from it. Results Loss of PRDX1 in vivo promotes collagen remodelling known to promote breast cancer progression. PRDX1 inactivation in MFs occurs via SRC-induced phosphorylation of PRDX1 TYR194 and not through the expected direct oxidation of CYS52 in PRDX1 by ROS. TYR194-phosphorylated PRDX1 fails to bind to lysyl oxidases (LOX) and leads to the accumulation of extracellular LOX proteins which supports enhanced collagen remodelling associated with breast cancer progression. Conclusions This study reveals a cell type-specific tumour suppressive role for PRDX1 that is supported by survival analyses, depending on PRDX1 protein levels in breast cancer cohorts.
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