Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Medical Physics, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Cancer Med. 2024 Jan;13(2):e6987. doi: 10.1002/cam4.6987.
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.
简介：三阴性乳腺癌（TNBC）被认为是乳腺癌（BC）中最具异质性的类型，其预后比其他亚型差。线粒体动力学作为肿瘤发生的中介物，通过适应细胞微环境发挥着重要作用。然而，线粒体动力学与代谢表型之间的关系在不同的研究和 BC 模型中存在差异和分歧。因此，本研究旨在探讨线粒体动力学在 TNBC 耐药性和肿瘤发生中的作用。
方法：采用 Wst-8 试验检测 HCC38、MDA-MB-231（TNBC）和 MCF-7（管腔）对阿霉素的敏感性。利用共聚焦显微镜和 FACS 定量测定线粒体膜电位（ΔφM）、线粒体自噬和活性氧（ROS）的产生。采用安捷伦 Seahorse XF 分析仪测量代谢特征。对 107 例接受新辅助化疗（NAC）前后的 BC 患者的样本进行 DRP1、Parkin 和 p62 的免疫组化染色。
结果：MDA-MB-231 是一种对阿霉素敏感性降低的 TNBC 细胞系，其 ΔφM 降低，通过氧化磷酸化（OXPHOS）为基础的代谢来增强线粒体自噬以维持 ROS 的产生。HCC38 是一种对阿霉素敏感的细胞系，其 ΔφM 或线粒体自噬没有改变。然而，它表现出 ROS 产生和糖酵解的增加。临床病理研究表明，DRP1 的预处理（NAC 前）表达在 TNBC 中具有显著意义，而在激素受体阴性组中 Parkin 的预处理表达也具有显著意义。此外，低水平的 p62 似乎是无复发生存的危险因素。
结论：我们的研究结果表明，线粒体自噬与更差的临床预后之间的相互作用，以及 OXPHOS 代谢促进了 TNBC 的化疗耐药性。线粒体分裂在 TNBC 中很常见。这些发现表明，针对 TNBC 中独特的线粒体代谢和动力学可能为 TNBC 患者提供一种新的治疗策略。
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