Kondakova Irina, Sereda Elena, Sidenko Evgeniya, Vtorushin Sergey, Vedernikova Valeria, Burov Alexander, Spirin Pavel, Prassolov Vladimir, Lebedev Timofey, Morozov Alexey, Karpov Vadim
Tomsk National Research Medical Center, Cancer Research Institute, Russian Academy of Sciences, 634009 Tomsk, Russia.
Department of Biochemistry and Molecular Biology, Faculty of Medicine and Biology, Siberian State Medical University, 634050 Tomsk, Russia.
Cancers (Basel). 2025 Jan 6;17(1):159. doi: 10.3390/cancers17010159.
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.
Bioinformatic analysis of proteasome subunit () 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.
BC subtypes demonstrate differing proteasome subunit expression pattern and strong 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.
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.
蛋白酶体可降解细胞内蛋白质。已鉴定出不同的蛋白酶体形式。蛋白酶体抑制剂用于癌症治疗，并且正在开发针对特定蛋白酶体形式的新型药物。乳腺癌（BC）的治疗取决于肿瘤的亚型，该亚型由Ki67、HER-2、雌激素和孕激素受体的表达水平决定。特定蛋白酶体形式的存在与决定BC亚型的蛋白质之间的关系仍不清楚。在此，我们使用来自144个数据集的19145个肿瘤样本以及159例不同BC亚型患者的组织中的基因表达数据，研究了蛋白酶体的活性和表达与BC亚型标志物水平之间的关联。
对BC中蛋白酶体亚基（）基因表达进行生物信息学分析。通过qPCR研究BC细胞系中的蛋白酶体异质性。通过蛋白质印迹法评估细胞和患者组织裂解物中的蛋白酶体组成。使用荧光底物研究蛋白酶体活性。通过免疫组织化学确定BC分子亚型。
BC亚型在肿瘤中表现出不同的蛋白酶体亚基表达模式和强烈的共相关性。与相邻组织相比，BC中胰凝乳蛋白酶样和半胱天冬酶样蛋白酶体活性显著增加。BC亚型肿瘤组织中蛋白酶体的亚基组成各不相同。回归分析表明蛋白酶体活性与Ki67、雌激素受体和孕激素受体的表达之间呈正相关。
BC亚型在蛋白酶体库中表现出差异。蛋白酶体活性、激素受体和Ki67之间的相关性表明可能存在相互影响。所得结果有助于开发用于BC治疗的新型药物组合。
