Chemoprevention of triple-negative breast cancer originating from cancer stem cells using OXPHOS inhibitors

We and other researchers have recently demonstrated in vitro that chemoresistant and stem-like triple-negative breast cancer cells preferentially obtain energy through mitochondrial oxidative phosphorylation (OXPHOS) compared to their chemosensitive counterparts, which undergo glycolysis. Proteomic profiling revealed several possible survival mechanisms for the resistant phenotype, including OXPHOS-associated pathways. Since metastasis and poor clinical prognosis are often associated with the dormant subset of slow-growing cancer stem cells (CSCs), we treated tumor models derived from mammospheres with pre-selected bactericidal antibiotics-OXPHOS inhibitors - AMX, FSS and others. Our results demonstrate significant inhibition of tumor growth in the inhibitor-treated groups compared to the placebo-treated group. Furthermore, this inhibition was more pronounced in tumors derived from CSCs than in tumors derived from chemosensitive cancer cells prone to glycolysis, further emphasizing the role of OXPHOS in CSCs. Since CSCs are often associated with a pool of chemoresistant OXPHOS-dependent cells, we conducted a chemoprevention experiment in which nude mice were given the above-mentioned inhibitors for several weeks, followed by injection with CSC-like cells (mammospheres) to create tumors. Our results showed a slowdown in tumor growth in the group of mice that had previously received these inhibitors, compared to mice that received a placebo. Thus, our experiments may be of interest for modeling the prevention of OXPHOS-dependent breast tumors.