Shashova Elena E, Lyupina Yulia V, Glushchenko Svetlana A, Slonimskaya Elena M, Savenkova Olga V, Kulikov Alexey M, Gornostaev Nikolay G, Kondakova Irina V, Sharova Natalia P
Department of Experimental Oncology, Cancer Research Institute of Siberian Branch of Russian Academy of Medical Sciences, Tomsk, Russia.
Department of Biochemistry of Ontogenesis Processes, NK Koltsov Institute of Developmental Biology of Russian Academy of Sciences, Moscow, Russia.
PLoS One. 2014 Oct 17;9(10):e109933. doi: 10.1371/journal.pone.0109933. eCollection 2014.
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.
乳腺癌是世界上最常见的四种肿瘤疾病之一。此外，在世界经济发达地区的女性人群中，乳腺癌是癌症相关死亡的主要原因之一。到目前为止，发现乳腺癌发展的新机制对于探索可能制定治疗方法的新领域非常重要。本研究的目的是调查蛋白酶体（其可切割多达90%的细胞蛋白并调节众多细胞过程）在乳腺癌发展机制中的作用。研究了106例患者乳腺癌组织及癌旁组织中的蛋白酶体特征，以及检测到的蛋白酶体参数与临床病理因素的关系。通过荧光肽Suc-LLVY-AMC的水解来评估蛋白酶体类胰凝乳蛋白酶活性。通过蛋白质印迹法和免疫组织化学法研究蛋白酶体亚基的表达。在肿瘤中检测到了广泛的类胰凝乳蛋白酶活性范围。106例患者中有76例的肿瘤活性高于癌旁组织。广义线性模型的多重分析发现，在雌激素α受体缺失的情况下，肿瘤生长与肿瘤中蛋白酶体免疫亚基LMP2和蛋白酶体激活剂PA700的表达增强有关（置信区间为95%）。此外，通过该分析我们在癌旁组织中检测到一些现象，这些现象对于雌激素α受体缺失情况下的肿瘤生长和淋巴结转移进展很重要。这些现象与激活剂PA700和免疫亚基LMP7的表达增强有关。因此，在肿瘤细胞中没有雌激素α受体的患者中，乳腺癌的发展与免疫蛋白酶体形式和激活剂PA700的功能有关。这些结果可能为这类健康恢复预后最差的患者寻找新的治疗方法指明一个方向。
