The differentiation status of breast cancer cells, its association with metastasis and the production of cytokines by the tumor in various molecular subtypes

Aim. To investigate the relationship between the differentiation status of breast cancer (BC) tumor cells (TC) of various molecular subtypes, the ability to metastasize, and the modulation of various cytokines in BC samples in vitro.
Materials and methods. Biopsies from invasive breast carcinoma of a non-specific type in 50 women, classified by the presence (Met+) and absence (Met–) of metastases in regional lymph nodes, were examined and categorized into 4 groups based on their molecular subtypes: luminal A (Lum A), luminal B (Lum B), HER2/neu positive (HER2+), and triple negative (TN). Using enzyme-linked immunosorbent assay, spontaneous and mitogen complex-stimulated (MC) production of 14 cytokines was determined in the supernatant of cultured BC samples (IL-2, IL-6, IL-8, IL-10, IL-17, IL-18, IL-1β, IL-1Ra, TNF-α, IFN-γ, G-CSF, GM-CSF, VEGF, and MCP-1), on the basis of which the index of the MC effect (IMCE) on cytokine production was calculated. The effect of stimulating the differentiation of TC was evaluated on the basis of cytomorphological criteria for reducing the relative content of low-grade cells (LGC) in BC samples.
Results. A statistically significant decrease in the relative content of LGC under the influence of MC was detected in the Met+ and Met– groups. MC had a differentiating effect in luminal and HER2-positive subtypes, while in TN breast cancer samples there was only a downward trend in the proportion of LGC. To assess the role of cytokines in the mechanism of the differentiating effect of MC on LGC, a neural network analysis of IMCE in the relationship of various cytokines was carried out. According to the results obtained, in Lum A, the leading role in the manifestation of the differentiation effect was associated with IL-1Ra and IL-6; in Lum B, with MCP-1 and GM-CSF; in HER2+, with IFN-γ and MCP-1, and in TN – with IL-1β and IL-6.
Conclusion. The data obtained indicate that the immune mechanisms mediating the differentiating MC effect on BC may vary in different molecular subtypes of BC.

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