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Cellular and Molecular Biology

Peroxiredoxin-1 Tyr194 phosphorylation regulates LOX-dependent extracellular matrix remodelling in breast cancer

Abstract

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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Fig. 1: Loss of PRDX1 in MFs promotes collagen remodelling in mammary glands of a syngeneic mouse model vivo and MFs in vitro.
Fig. 2: MDA-MB-231 cancer-conditioned media increases phosphorylation of Y194 PRDX1.
Fig. 3: LOX secretion is increased in PRDX1-deficient and cancer-conditioned media-treated MFs.
Fig. 4: Prdx1 binds LOX family proteins regulating collagen cross-linking.
Fig. 5: PRDX1 protein levels and SRC Tyr416 protein phosphorylation correlate with the overall survival of breast cancer patients.

Data availability

Data will be available as needed.

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Acknowledgements

The results shown here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. Flow Cytometry Cell Sorting was performed by Joan Brozick at the Flow Cytometry Core on a BD FACSAria Fusion system. The Flow Core is supported by contributions from generous philanthropists through the MWRI Foundation of Pittsburgh, PA.

Funding

This work was supported by R01 CA131350 (CAN), CDMRP/BCRP BC095803 (CAN), Howard Hughes Medical Institute Gilliam Predoctoral fellowship PREDC 59008467 (SA), P30-DK072506, (UPMC Hillman Cancer Center), Cotswold Foundation postdoctoral fellowship (JS). This funding body had no role in the design of the study or collection analysis, and interpretation of data and in writing the manuscript.

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SA, JS and CN designed, performed analysed and interpreted experiments and wrote the manuscript. BH, LW and MW performed experiments. HW and AF interpreted the data.

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Correspondence to Carola A. Neumann.

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Attaran, S., Skoko, J.J., Hopkins, B.L. et al. Peroxiredoxin-1 Tyr194 phosphorylation regulates LOX-dependent extracellular matrix remodelling in breast cancer. Br J Cancer 125, 1146–1157 (2021). https://doi.org/10.1038/s41416-021-01510-x

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