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Tumors are the most types of diseases that still kill human life, many treatments have been used, including chemotherapy and others, but the side effects were exponentially severe. The research has tended towards the use of nanoparticles and plant products. The nanoparticles used in the current study are CeO2 with a size of ≤5 nm in addition to the use of Retinoic acid (RA) as a synthetic natural chemical. The role of these materials in breast cancer has been investigated by using cancerous and natural cell lines by assay MTT and via qPCR technique. Five concentrations were used for each of the CeO2NP (0, 52, 70,100, 150, 200 µg / ml) and for RA (0,150,180,200,250,300µg / ml). To discuss the relationship between the joint actions of the two articles, they were merged after taking three concentrations for each substance and the CompuSyn software was adopted to determine that. The Results revealed that there is cytotoxicity of the two substances CeO2NP and RA on the cell lines (MCF-7, CaL51, & HBL-100) and that the levels of vitality decrease with increasing concentration, except for the normal cell line HBL-100, that their vitality increases with the increase in the concentration of the substance. The combined treatment of both substances did not show synergistic activity on the three cell lines. After 48 hours, CeO2NP and RA were caused different cytopathic changes in cell lines, those changes are outcome of biochemical and molecular events happening in apoptotic cells. In addition, cell death was seen after staining with the AO-EB dye after being treated for 48 hours. The current study examined the cellular pathways that depend on activating the gene expression of the caspase genes (Caspase 8& 9) in two cell lines (Cal51, HBL-100) showed that the CeO2NP have apoptosis-promoting effects by activation of the Caspase8 in both the normal HBL-100 and carcinogenic lines Cal51, while the retinoic acid, its action was similar to CeO2NP by activating Caspase8 in the normal cell line HBL-100, except that it stimulated the intrinsic pathway of apoptosis in cell line Cal51 through activation of the Caspase9. Our finding, that RA have a similar cytotoxicity on cell lines, while CeO2NP was more effective on MCF-7 and CaL51 lines, despite its obvious toxicity on normal cell line HBL-100. The substances did not show any synergy with each other when they were combined and treated with cells. It was also found that each substance has a different cell death pathway.