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.

中文翻译：

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Peroxiredoxin-1 Tyr194 磷酸化调节乳腺癌中 LOX 依赖性细胞外基质重塑

 背景

过氧化还原蛋白 1 (PRDX1) 属于丰富的过氧化物酶家族，其在癌症中的作用尚未确定。虽然小鼠敲除研究证明 PRDX1 在癌细胞异种移植物中具有肿瘤抑制作用，但结果表明 PRDX1 作为药物靶点。这种表型差异可能源于 PRDX1 在某些细胞类型或肿瘤进展阶段中的不同作用。

 方法

我们利用同基因小鼠模型 (BALB/c) 和从中获得的乳腺成纤维细胞 (MF) 证明了 PRDX1 的重要细胞自主功能。

 结果

体内 PRDX1 的缺失会促进胶原蛋白重塑，从而促进乳腺癌进展。 MF 中 PRDX1 失活是通过 SRC 诱导的 PRDX1 TYR194 磷酸化发生的，而不是通过 ROS 对 PRDX1 中 CYS52 的预期直接氧化发生的。 TYR194 磷酸化的 PRDX1 无法与赖氨酰氧化酶 (LOX) 结合，并导致细胞外 LOX 蛋白的积累，从而支持与乳腺癌进展相关的增强的胶原蛋白重塑。

 结论

这项研究揭示了 PRDX1 的细胞类型特异性肿瘤抑制作用，这一作用得到了生存分析的支持，具体取决于乳腺癌队列中的 PRDX1 蛋白水平。