Targeting DRP1 mediated mitochondrial metabolism as a novel treatment strategy for triple negative breast cancer (TNBC)

Abstract Background Triple-negative breast cancer (TNBC), the most heterogeneous type of breast cancer, has a high risk of recurrence and a shorter overall survival compared to the other subtypes. The ability of mitochondria to flexibly adapt to their microenvironment makes them crucial tumorigenesis mediators. in this study, we explored the role of mitochondrial dynamics in TNBC drug resistance and tumorigenesis. Methods The doxorubicin sensitivity of TNBC cell lines HCC38 and MDA-MB-231, as well as luminal cell line MCF-7, was determined using the Wst-8 test. Confocal microscopy and FACS were used to measure the mitochondrial membrane potential (ΔφM), mitophagy, and ROS generation of HCC38 and MDA-MB-231. Agilent Seahorse XF Analyzers measured metabolic characteristics of HCC38, MDA-MB 231and MCF-7. DRP1, Parkin, and p62 immunohistochemistry staining were performed by using both core needle biopsy samples and the samples removed at the surgery of 108 primary breast cancer patients who underwent surgery after neoadjuvant chemotherapy (NAC). Results MDA-MB-231, a doxorubicin resistant TNBC cell line, reduced ΔφM and enhanced mitophagy to maintain ROS production with OXPHOS-based metabolism. HCC38, a cell sensitive to doxorubicin, showed no change in ΔφM and mitophagy, with glycolysis as the primary metabolic characteristic and an uncontrolled rise in ROS production. Clinicopathological studies have found that DRP1 before NAC (pre-DRP1) was highly expressed in TNBC and groups with KI67 greater than 20% (p = 0.009, 0.016). Parkin was also highly expressed in HR- and high KI67 groups (p = 0.013 and 0.005) and the expression of p62 was higher only in high Ki67 groups (p = 0.003). There was a trend in the non-pCR group for DRP1 to decrease and p62 to increase after treatment, although the difference was not statistically significant. Conclusion Our findings showed that mitophagy, in association with OXPHOS metabolism, promoted chemotherapy resistance and tumor growth in TNBC. The lack of effective therapeutic options for patients with TNBC remains a major challenge, therefore, targeting unique mitochondria metabolic signatures within tumor cells can potentially offer another therapeutic strategy for this highly aggressive disease.