Exosomes are small vesicles which are produced by the cells and released into the surrounding space. They can transfer biomolecules into recipient cells. The main goal of the work was to study the exosome involvement in the cell transfer of hormonal resistance. The experiments were performed on in vitro cultured estrogen-dependent MCF-7 breast cancer cells and MCF-7 sublines resistant to SERM tamoxifen and/or biguanide metformin, which exerts its anti-proliferative effect, at least in a part, via the suppression of estrogen machinery. The exosomes were purified by differential ultracentrifugation, cell response to tamoxifen was determined by MTT test, and the level and activity of signaling proteins were determined by Western blot and reporter analysis. We found that the treatment of the parent MCF-7 cells with exosomes from the resistant cells within 14 days lead to the partial resistance of the MCF-7 cells to antiestrogen drugs. The primary resistant cells and the cells with the exosome-induced resistance were characterized with these common features: decrease in ERα activity and parallel activation of Akt and AP-1, NF-κB, and SNAIL1 transcriptional factors. In general, we evaluate the established results as the evidence of the possible exosome involvement in the transferring of the hormone/metformin resistance in breast cancer cells.

Межклеточные взаимодействия и развитие гормональной резистентности клеток рака молочной железы

Objective: to study the role of the intercellular interactions in the progression of the cancer cells resistance to metformin, a biguanide antidiabetic drug exhibited the marked anti-tumor activity.Results. Earlier we have demonstrated the effect of horizontal transferring of hormonal resistance of breast cancer cells from cell to cell, and showed the key role of exosomes on the transferring of the resistance. Here we have shown the effect of the horizontal transferring of metformin resistance in breast cancer cells – similar to the progression of hormonal resistance. We found that horizontal transferring of the metformin resistance is mediated via exosomes secreted by the resistant cells. The proteome analysis of the exosomes revealed several proteins differentially expressed in the exosomes of metformin-resistant cells and associated with the regulation of cell response to apoptotic drugs.Conclusions. Totally, the data presented demonstrate the new mechanism of the development of the cancer cell resistance based on the intercellular interactions, opening the new insights in the target therapy of breast cancer.

ЭКЗОСОМЫ И ФОРМИРОВАНИЕ РЕЗИСТЕНТНОГО ФЕНОТИПА ОПУХОЛЕВЫХ КЛЕТОК