Abstract
Breast cancer is one of four oncology diseases that are most widespread in the world. Moreover, breast cancer is one of leading causes of cancer-related deaths in female population within economically developed regions of the world. So far, detection of new mechanisms of breast cancer development is very important for discovery of novel areas in which therapy approaches may be elaborated. The objective of the present study is to investigate involvement of proteasomes, which cleave up to 90% of cellular proteins and regulate numerous cellular processes, in mechanisms of breast cancer development. Proteasome characteristics in 106 patient breast carcinomas and adjacent tissues, as well as relationships of detected proteasome parameters with clinical-pathological factors, were investigated. Proteasome chymotrypsin-like activity was evaluated by hydrolysis of fluorogenic peptide Suc-LLVY-AMC. The expression of proteasome subunits was studied by Western-blotting and immunohistochemistry. The wide range of chymotrypsin-like activity in tumors was detected. Activity in tumors was higher if compared to adjacent tissues in 76 from 106 patients. Multiple analysis of generalized linear models discovered that in estrogen α-receptor absence, tumor growth was connected with the enhanced expression of proteasome immune subunit LMP2 and proteasome activator PA700 in tumor (at 95% confidence interval). Besides, by this analysis we detected some phenomena in adjacent tissue, which are important for tumor growth and progression of lymph node metastasis in estrogen α-receptor absence. These phenomena are related to the enhanced expression of activator PA700 and immune subunit LMP7. Thus, breast cancer development is connected with functioning of immune proteasome forms and activator PA700 in patients without estrogen α-receptors in tumor cells. These results could indicate a field for search of new therapy approaches for this category of patients, which has the worst prognosis of health recovery.
Highlights
Proteasomes, ‘‘ubiquitous’’ protease systems, regulate numerous cellular processes by protein degradation and/or peptide production in all organs and tissues including malignant tumors [1,2,3,4,5]
We focused our attention on the research of a type of ER, since this type of receptors is involved in the process of cellular proliferation [27]
Distribution of proteasome subunits in tumor tissue cells The distribution of the total proteasome pool was investigated according to the expression of a1,2,3,5,6,7 subunits included in all proteasome forms
Summary
Proteasomes, ‘‘ubiquitous’’ protease systems, regulate numerous cellular processes by protein degradation and/or peptide production in all organs and tissues including malignant tumors [1,2,3,4,5]. Among proteasome forms, the special role in tumor fate belongs to immune proteasomes. Substrate binding pockets of immune proteasomes differ from those of constitutive ones [7]. Immune proteasomes display the altered cleavage site preference with a strong predominance to cleave behind basic or hydrophobic residues that represent the correct C terminus of a major histocompatibility complex (MHC) class I epitope. Antigenic epitopes produced from tumor proteins are transported with MHC class I molecules on the tumor cell surface for their further presentation to cytotoxic T-CD8+ lymphocytes. Immune proteasomes display anticancer function by forming antigenic epitopes in tumor cells. Immune proteasomes may play another role and favor cell survival by quenching the oxidative stress [8,9]
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