P38: The role of intercellular interactions in the regulation of hormonal sensitivity of breast cancer cells

Abstract

The efficiency of endocrine therapy for tumors is limited by the development of hormone resistance and progression of tumor cells to hormone-independent phenotype. Among these tumors – breast cancers, for which hormone therapy is one of the most common and effective methods of treatment, but only in cases, when the tumors retain their hormonal dependence. The mechanism of hormonal independence was found to be based on the fundamental properties of cancer cell including both downregulation of specific hormone receptors, and affecting of intracellular signalling, particularly – estrogen-independent growth signaling pathways. However, the role of the intercellular interactions in the progression of hormonal resistance is still unclear. We hypothesize, that the formation of the clone of the hormone-resistant cells in the tumor, and the subsequent common growth of the hormone-resistant and sensitive cells may lead to spread the hormonal resistance to the sensitive cells – as a result of the secretion of the specific factors acting in the paracrine manner or via the direct cell–cell contacts. Here, 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. For this purpose MCF-7/T cells were 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. The GFP expression should allow to distinguish the resistant and parental cells during co-cultivation. To study the influence of the co-cultivation on the cell sensitivity to tamoxifen the parent MCF-7 cells (GFP-negative) were co-cultivate with the resistant MCF-7/T/GFP+/cells for 10 days, then the cells were treated with tamoxifen and the efficiency of growth inhibitory tamoxifen action was determined. We found, that the co -cultivation of the parent and resistant cells lead to increase in the resistance of the parent cell to tamoxifen, indicating the important role of the contacts, direct or indirect, between hormone sensitive and resistant cells in the development of hormone resistance. In general, we evaluate the established results as the first evidence of the possible involvement of the cell–cell underrelations in the realization of the hormonal response, and suppose that the next investigations will give a new insights in the molecular mechanisms of this effects and its role in the formation of the hormone-resistant phenotype of the tumors.