Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt.
Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia.
Eur J Pharmacol. 2024 Jun 15;973:176568. doi: 10.1016/j.ejphar.2024.176568. Epub 2024 Apr 9.
Triple negative breast cancer (TNBC) has the worst prognosis among breast cancer subtypes. It is characterized by lack of estrogen, progesterone and human epidermal growth factor 2 receptors, and thus, have limited therapeutic options. Autophagy has been found to be correlated with poor prognosis and aggressive behaviour in TNBC. This study aimed to target autophagy in TNBC via a novel approach to inhibit TNBC progression.
Immunoblotting and confocal microscopy were carried out to examine the effect of tumor microenvironmental stressors on autophagy. Cellular proliferation and migration assays were used to test the effect of different autophagy inhibitors and standard chemotherapy alone or in combination. In vivo xenograft mouse model was utilized to assess the effect of autophagy inhibitors alone or in combination with Paclitaxel. High resolution mass spectrometry based proteomic analysis was performed to explore the mechanisms behind chemoresistance in TNBC. Lastly, immunohistochemistry was done to assess the correlation between autophagy related proteins and clinical characteristics in TNBC tissue specimens.
Metabolic stressors were found to induce autophagy in TNBC cell lines. Autophagy initiation inhibitors, SAR405 and MRT68921, showed marked synergy in their anti-proliferative activity in both chemosensitive and chemoresistant TNBC cell models. Paradoxically, positive expression of autophagosome marker LC3 was shown to be associated with better overall survival of TNBC patients.
In this study, a novel combination between different autophagy inhibitors was identified which inhibited tumor cell proliferation in both chemosensitive and chemoresistant TNBC cells and could result in development of a novel treatment modality against TNBC.
三阴性乳腺癌（TNBC）是乳腺癌亚型中预后最差的一种。其特点是缺乏雌激素、孕激素和人表皮生长因子 2 受体，因此治疗选择有限。自噬已被发现与 TNBC 的不良预后和侵袭性行为相关。本研究旨在通过一种新的方法靶向 TNBC 的自噬，以抑制 TNBC 的进展。
采用免疫印迹和共聚焦显微镜技术检测肿瘤微环境应激源对自噬的影响。细胞增殖和迁移实验用于测试不同自噬抑制剂以及单独或联合标准化疗的作用。体内异种移植小鼠模型用于评估自噬抑制剂单独或与紫杉醇联合的作用。采用基于高分辨率质谱的蛋白质组学分析方法探讨 TNBC 化疗耐药的机制。最后，进行免疫组织化学检测以评估自噬相关蛋白与 TNBC 组织标本临床特征之间的相关性。
代谢应激源被发现可诱导 TNBC 细胞系发生自噬。自噬起始抑制剂 SAR405 和 MRT68921 在化疗敏感和耐药的 TNBC 细胞模型中均表现出显著的协同抗增殖活性。矛盾的是，自噬体标记物 LC3 的阳性表达与 TNBC 患者的总生存时间延长相关。
在这项研究中，鉴定出一种新的不同自噬抑制剂联合用药方案，可抑制化疗敏感和耐药的 TNBC 细胞的肿瘤细胞增殖，并可能为 TNBC 的治疗提供新的治疗方法。
