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Imbalance in the cellular redox system is thought to be associated with the induction and progression of breast cancers, and heme proteins may regulate the redox balance. Cytochrome <i>b₅</i> (Cyt <i>b₅</i>) is a small mitochondrial heme protein. Its function and regulating mechanism in breast cancer remain unknown. In this study, we elucidated the level of endogenous oxidative stress in breast cancer cells, MCF-7 cells (hormone receptor-positive cells) and MDA-MB-231 cells (triple-negative cells), and investigated the difference in Cyt <i>b₅</i> content. Based on the low content of Cyt <i>b₅</i> in MDA-MB-231 cells, the overexpression of Cyt <i>b₅</i> was found to regulate the oxidative stress and apoptosis cascades, including ERK1/2 and Akt signaling pathways. The overexpressed Cyt <i>b₅</i> MDA-MB-231 cells were shown to exhibit decreased oxidative stress, less phosphorylation of ERK1/2 and Akt, and less cleavage of caspases 3 and 9 upon treatment with H₂O₂, as compared to those of normal MDA-MB-231 cells. Moreover, the overexpressed Cyt <i>b₅</i> most likely functioned by interacting with its protein partner, Cyt <i>c</i>, as suggested by co-immunoprecipitation studies. These results indicated that Cyt <i>b₅</i> has different effects on breast cancer cells of different phenotypes, which provides useful information for understanding the multiple roles of Cyt <i>b₅</i> and provides clues for clinical treatment.