AI Article Synopsis

  • Triple-negative breast cancer (TNBC) is a highly variable and aggressive subtype of breast cancer, and this study investigates how mitochondrial dynamics contribute to TNBC's resistance to chemotherapy and tumor growth.
  • The research involved testing TNBC cell lines for sensitivity to the drug doxorubicin, analyzing mitochondrial function, and examining expressions of various proteins in patient samples before and after treatment.
  • Results showed that the TNBC cell line MDA-MB-231 has altered mitochondrial behavior that helps it resist doxorubicin, while findings suggest that specific protein expressions correlate with poorer clinical outcomes, highlighting the complex role of mitochondrial dynamics in TNBC.

Article Abstract

Introduction: Triple-negative breast cancer (TNBC), recognized as the most heterogeneous type of breast cancer (BC), exhibits a worse prognosis than other subtypes. Mitochondria dynamics play a vital role as mediators in tumorigenesis by adjusting to the cell microenvironments. However, the relationship between mitochondrial dynamics and metabophenotype exhibits discrepancies and divergence across various research and BC models. Therefore, this study aims to explore the role of mitochondrial dynamics in TNBC drug resistance and tumorigenesis.

Methods: The Wst-8 test was conducted to assess doxorubicin sensitivity in HCC38, MDA-MB-231 (TNBC), and MCF-7 (luminal). Confocal microscopy and FACS were used to quantify the mitochondrial membrane potential (ΔφM), mitophagy, and reactive oxygen species (ROS) production. Agilent Seahorse XF Analyzer was utilized to measure metabolic characteristics. Dynamin-related protein-1 (DRP1), Parkin, and p62 immunohistochemistry staining were performed using samples from 107 primary patients with BC before and after neoadjuvant chemotherapy (NAC).

Results: MDA-MB-231, a TNBC cell line with reduced sensitivity to doxorubicin, reduced ΔφM, and enhanced mitophagy to maintain ROS production through oxidative phosphorylation (OXPHOS)-based metabolism. HCC38, a doxorubicin-sensitive cell line, exhibited no alterations in ΔφM or mitophagy. However, it demonstrated an increase in ROS production and glycolysis. Clinicopathological studies revealed that pretreatment (before NAC) expression of DRP1 was significant in TNBC, as was pretreatment expression of Parkin in the hormone receptor-negative group. Furthermore, low p62 levels seem to be a risk factor for recurrence-free survival.

Conclusion: Our findings indicated that the interplay between mitophagy, linked to a worse clinical prognosis, and OXPHOS metabolism promoted chemotherapy resistance in TNBC. Mitochondrial fission is prevalent in TNBC. These findings suggest that targeting the unique mitochondrial metabolism and dynamics in TNBC may offer a novel therapeutic strategy for patients with TNBC.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10854452PMC
http://dx.doi.org/10.1002/cam4.6987DOI Listing

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