Interaction of phenotypic sublines isolated from triple-negative breast cancer cell line MDA-MB-231 modulates their sensitivity to paclitaxel and doxorubicin in 2D and 3D assays

Breast cancer is a rapidly evolving, multifactorial disease that accumulates numerous genetic and epigenetic alterations. These result in molecular and phenotypic heterogeneity within the tumor, the complexity of which is further amplified through specific interactions between cancer cells. We aimed to analyze cell phenotypic sublines and the influence of their interaction on drug resistance, spheroid formation, and migration. Seven sublines were derived from the MDA-MB-231 breast cancer cell line using a multiple-cell suspension dilution. The growth rate, CD133 receptor expression, migration ability, and chemosensitivity of these sublines to anticancer drugs doxorubicin (DOX) and paclitaxel (PTX) were determined. Three sublines (F5, D8, H2) have been chosen to study their interaction in 2D and 3D assays. In the 2D model, the resistance of all sublines composition to DOX decreased, but in the 3D model, the resistance of all sublines except H2, increased to both PTX and DOX. In the 3D model, the combined sublines F5 and D8 had higher resistance to DOX and statistically significantly lower resistance for PTX compared to the control. The interaction between cancer stem-like cells (F5) and increased migration cells (D8) increased resistance to PTX in cell monolayer and increased resistance against both DOX and PTX in the spheroids. The interaction of DOX-resistant (H2) cells with other cell subpopulations (D8, F5, HF) decreased the resistance to DOX in cell monolayer and both DOX and PTX in spheroids.