SUCLA2-USP10 interaction rather than SUCLA2 alone correlates with metastasis in breast cancer patients

Abstract

Aims: Translating pre-clinical findings into clinical evidence is essential for cancer research. Although succinyl-CoA ligase ADP-forming subunit beta (SUCLA2) has been implicated in metastasis through stress granule assembly in pre-clinical models, direct clinical evidence linking SUCLA2-alone or in interaction with stress granule components such as ubiquitin-specific peptidase 10 (USP10)-to distant metastasis-free survival (DMFS) remains limited. This study aimed to evaluate whether the SUCLA2-USP10 interaction correlates with breast cancer DMFS and whether treatment modifies this association.

Methods: We analyzed four independent breast cancer cohorts with DMFS data (GSE17705, GSE45255, GSE7390, and GSE11121). Patients were stratified into four subgroups based on median SUCLA2 and USP10 expression levels: low-SUCLA2/low-USP10 (LL), low-SUCLA2/high-USP10 (LH), high-SUCLA2/low-USP10 (HL), and high-SUCLA2/high-USP10 (HH). Stratified Cox regression was applied, with cohort as the stratification factor, to examine whether the prognostic impact of these subgroups differed between treated and untreated patients.

Results: A significant interaction was observed between treatment status and SUCLA2-USP10 subgroup membership, specifically for the LH subgroup (p = 0.00038). In untreated patients, the LH subgroup exhibited a significantly higher risk for DMFS (HR = 2.45), whereas in treated patients, this elevated risk was completely abrogated (HR = 0.71). Neither SUCLA2 nor USP10 alone showed a consistent association with DMFS across the four cohorts.

Conclusion: These findings provide clinical evidence that the SUCLA2-USP10 interaction, rather than either factor alone, correlates with breast cancer DMFS. The treatment-modulated risk reversal observed in the LH subgroup supports the development of anti-metastatic strategies targeting this interaction.

Keywords

Breast cancer / metastasis / mitochondrial metabolism / stress granule / SUCLA2 / USP10

Authors contribution

He X: Conceptualization, investigation, formal analysis, writing-original draft. Shao Y: Formal analysis. Sun X: Conceptualization, formal analysis. All authors have read and approved the final version of the manuscript.

Conflicts of interest

The authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The datasets (GSE17705, GSE45255, GSE7390, GSE11121) analyzed during the current study are available in the GEO repository: https://www.ncbi.nlm.nih.gov/geo/.

Funding

This work has been partially supported by the grants from the United States Center for Disease Control and Prevention (CDC) grant U01OH012778 and the National Natural Science Foundation of China (12526210, 92570102, 62273364).

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