MYC Promotion of Oxidative Phosphorylation Enhances Chemotherapy Resistance in Triple-Negative Breast Cancer
Introduction. Triple-negative breast cancers (TNBCs) account for approximately fifteen percent of breast cancers, and they lack the presence of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). Because targeted therapies rely on the presence of at least one of the previously mentioned receptors, TNBC treatment is limited to chemotherapy and surgery1-3. It has been hypothesized that certain TNBC cells are resistant to chemotherapy due to their “stem-like” ability to alter their metabolism. These cancer stem cells (CSCs) differ from other cancer cells, because studies have shown that they prefer oxidative phosphorylation to meet their energy needs, which is in contradiction to the Warburg effect1,2,4,5. Methods. Serial biopsies were analyzed for patients before and after neoadjuvant chemotherapy, and next generation sequencing was used to correlate amplification of genes with chemotherapy resistance. Sphere formation and aldehyde dehydrogenase assays were used to isolate CSCs and to measure “stemness” of cells. siRNA was used for the ablation of MYC. Oxidative phosphorylation was measured by measuring reactive oxygen species (ROS) and mitochondria-specific stains. The number of mitochondria in cells were measured by transmission electron microscopy (TEM). Western blot analysis was used to measure protein levels. Results. MYC expression was found to be amplified in chemotherapy resistant biopsies of TNBC patients. MYC ablation cell lines demonstrated reduced mammosphere formation2. Cells with increased levels of aldehyde dehydrogenase had higher concentrations of ROS and increased uptake of mitochondrial-specific stain. siRNA-ablated cell lines had fewer mitochondria, as seen on TEM2. Western blot analysis demonstrated that CSCs had increased levels of hypoxia-induced factor-1α (HIF-1α), however this was dependent on levels of ROS2. Conclusions. CSCs demonstrate MYC-amplification in TNBC. MYC-amplified cells show cancer stem-like qualities, including the ability to alter their metabolism to favor oxidative phosphorylation. Experimental data suggests that MYC accomplishes this by increasing the number of mitochondria within the cell. The resulting increase in ROS concentrations activates HIF-1α, which may farther contribute to the stem-like characteristics of CSCs.
- Camrada R, Zhou Z, Kohnz RA, et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nature Medicine. 2016; 22(4): 427-432.
- Lee K, Giltnane JM, Balko JM et al. MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells through regulation of mitochondrial oxidative phosphorylation. Cell Metabolism. 2017; 26(4): 633-647.
- McDonald ES, Clark AS, Tchou J, Zhang P, Freedman GM. Clinical Diagnosis and Management of Breast Cancer. Journal of Nuclear Medicine. 2016;57:9S-16S.
- Mishra P, Tang W, Putluri V, et al. ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming. Journal of Clinical Investigation. 2018;128(1):323-340.
- Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, Metabolism, and Cancer. Cancer Discovery. 2015;5(10):1024-1039.