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A Compendium of Co-regulated Protein Complexes in Breast Cancer Reveals Collateral Loss Events
Colm J Ryan1, Susan Kennedy2, Ilirjana Bajrami3
1School of Computer Science, University College Dublin, Dublin 4, Ireland; Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland.
Abstract:
Protein complexes are responsible for the bulk of activities within the cell, but how their behavior and abundance varies across tumors remains poorly understood. By combining proteomic profiles of breast tumors with a large-scale protein-protein interaction network, we have identified a set of 285 high-confidence protein complexes whose subunits have highly correlated protein abundance across tumor samples. We used this set to identify complexes that are reproducibly under- or overexpressed in specific breast cancer subtypes. We found that mutation or deletion of one subunit of a co-regulated complex was often associated with a collateral reduction in protein expression of additional complex members. This collateral loss phenomenon was typically evident from proteomic, but not transcriptomic, profiles, suggesting post-transcriptional control. Mutation of the tumor suppressor E-cadherin (CDH1) was associated with a collateral loss of members of the adherens junction complex, an effect we validated using an engineered model of E-cadherin loss.
Insights
This study reveals how protein complex abundance varies in breast tumors. It found that mutations in one protein subunit can decrease the expression of other complex members, often at the post-transcriptional level.
Area of Science:
- Molecular Biology
- Cancer Research
- Proteomics
Background:
- Protein complexes drive cellular functions, but their tumor-specific variations are unclear.
- Understanding protein complex behavior in cancer is crucial for targeted therapies.
Purpose of the Study:
- To identify protein complexes with altered abundance in breast cancer subtypes.
- To investigate the impact of genetic alterations on protein complex stability and expression.
Main Methods:
- Integrated proteomic data from breast tumors with protein-protein interaction networks.
- Identified 285 high-confidence protein complexes with correlated subunit abundance.
- Analyzed gene mutations and deletions in relation to complex member expression.
Main Results:
- Discovered specific protein complexes that are consistently under- or overexpressed in distinct breast cancer subtypes.
- Observed a 'collateral loss' phenomenon where mutations in one subunit reduce expression of other complex members.
- This collateral loss was primarily detected via proteomics, indicating post-transcriptional regulation.
Conclusions:
- Protein complex dysregulation is a key feature of breast cancer subtypes.
- Post-transcriptional mechanisms significantly influence protein complex integrity following genetic alterations.
- E-cadherin (CDH1) mutations exemplify collateral loss within the adherens junction complex.