Успехи молекулярной онкологии (Jun 2015)
Intercellular interactions and progression of hormonal resistance of breast cancer cells
Abstract
The main goal of the study is the analysis of the role of cell-cell interactions in the formation of the tumor cell resistance to hormonal drugs. About 70 % of breast tumors contain estrogen receptor (ER), a key molecular target for hormone (endocrine) therapy. However, the efficiency of endocrine therapy of breast cancer is limited by the development of hormone resistance which leads to progression of tumor cells to hormone-independent phenotype, increase in tumor malignancy and worse prognosis. Hormonal independence may be accompanied with the loss of the receptors, as well as with the another mechanisms including ligand-independent receptor activation, disbalance between receptor activators and repressors, stimulation of hormone-independent pathways. It is less known about the role of the intercellular interactions in the progression of hormonal resistance. Several studies demonstrate the involvement of cell junctions in the mediating of cell response to (anti) estrogens, however the significance of cell-cell contacts in the formation of hormonal resistance still not clear. Here we have hypothesized that the formation of the hormone resistance of tumors may be based, at least in part, on the transferring of the resistant phenotype from the resistant to hormone-sensitive cells – as a result of the secretion of the specific factors acting in the paracrine manner or via the direct cell-cell contacts. Using the estrogen-dependent breast cancer cells MCF-7 and the resistant subline MCF-7 / T developed by long-term cultivation of MCF-7 cells in the presence of antiestrogen tamoxifen, we investigated the possible changes in the hormonal sensitivity of these cells caused by the co-cultivation in vitro. To discern the cell cultures, the MCF-7 / T cells were previously transfected with the plasmid containing the gene of the green fluorescent protein (GFP), and GFP-positive hormone-resistant subline MCF-7 / T / GFP+ was developed. We showed that the co-cultivation of the parent and resistant cells lead to increase in the resistance of the parent cell to tamoxifen. To further explore the mechanism of such resistance, the analysis of the biological activity of exosomes prepared from the estrogen-sensitive and resistant cells was performed. The exosome preparations isolated from the resistant MCF-7 / T cells were found to induce the similar resistance in the recipient MCF-7 cells – in contrast to the control exosomes isolated from the MCF-7 cells. The subsequent cloning of these newly formed resistant cells showed that the cells retain the resistant phenotype for at least 80 days of cultivation. Totally, the results presented demonstrate the important role of cell-cell interactions in the progression of hormonal resistance, opening a new perspectives in the development of probable targets for breast cancer therapy.
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