Association of Proteasome Activity and Pool Heterogeneity with Markers Determining the Molecular Subtypes of Breast Cancer

Background: Proteasomes degrade intracellular proteins. Different proteasome forms were identified. Proteasome inhibitors are used in cancer therapy, and novel drugs directed to specific proteasome forms are developed. Breast cancer (BC) therapy depends on the subtype of the tumor, determined by the expression level of Ki67, HER-2, estrogen and progesterone receptors. Relationships between the presence of specific proteasome forms and proteins that determine the BC subtype remain unclear. Here, using gene expression data in 19,145 tumor samples from 144 datasets and tissues from 159 patients with different subtypes of BC, we investigated the association between the activity and expression of proteasomes and levels of BC subtype markers. Methods: Bioinformatic analysis of proteasome subunit (PSMB1-10) gene expression in BC was performed. Proteasome heterogeneity in BC cell lines was investigated by qPCR. By Western blotting, proteasome composition was assessed in cells and patient tissue lysates. Proteasome activities were studied using fluorogenic substrates. BC molecular subtypes were determined by immunohistochemistry. Results: BC subtypes demonstrate differing proteasome subunit expression pattern and strong PSMB8-10 co-correlation in tumors. A significant increase in chymotrypsin- and caspase-like proteasome activities in BC compared to adjacent tissues was revealed. The subunit composition of proteasomes in tumor tissues of BC subtypes varied. Regression analysis demonstrated a positive correlation between proteasome activities and the expression of Ki67, estrogen receptors and progesterone receptors. Conclusion: BC subtypes demonstrate differences within the proteasome pool. Correlations between the proteasome activity, hormone receptors and Ki67 indicate possible mutual influence. Obtained results facilitate development of novel drug combinations for BC therapy.