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Genetic and molecular heterogeneity, together with intrinsic and acquired resistance to therapy, represent the major obstacles to the successful treatment of different types of breast carcinoma. Increasing evidence demonstrates that SOX transcription factors in breast carcinomas could act both as oncogenes and tumor suppressors and have been associated with tumor stage and grade, poor prognosis, and therapy resistance. Both  SOX2  and  SOX18  over-expression has been correlated with poor prognosis in breast carcinomas, and these genes are recognized as potential antitumor targets. Our aim was to evaluate the effect of retinoic acid (RA), a well-known cyto-differentiating agent, on breast carcinoma cells  in vitro  and to investigate the potential of RA treatment to modify the expression of  SOX2  and  SOX18  genes. By applying various experimental approaches, we evaluated the effect of RA on basic cellular processes in SK-BR-3 and MCF7 breast carcinoma cell lines. We have shown that RA inhibits cell growth, reduces the number of Ki-67 positive cells, and causes cell-cycle arrest. RA effect was more prominent in SK-BR-3 cell line that lacks  SOX2  expression, including a higher decrease in cell viability, reduction in colony formation, and significant remodeling of cellular structure. We have shown that RA treatment led to the downregulation of  SOX2  expression in MCF7 cells and to the reduction of  SOX18  expression in both cell lines. By functional analysis, we showed that the anti-proliferative effect of RA in both cell lines was not based on the activity of stemness marker  SOX2 , pointing to a  SOX2 -independent mechanism of action. The ability of RA to reduce  SOX2/ SOX18   expression raises the possibility that these genes can be used as biomarkers to distinguish RA-responders from non-responders. Together, our study shows that the response of breast carcinoma cell lines to RA treatment may vary, highlighting that the development of RA-based therapy should consider differences in breast carcinoma subtypes.

Retinoic acid affects basic cellular processes and SOX2 and SOX18 expression in breast carcinoma cells