Feliz-Mosquea Yismeilin R, Wilson Adam S, Cruz-Diaz Nildris, Payne Valerie S, Cook Katherine L, Soto-Pantoja David R
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Department of Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Physiol Rep. 2025 Sep;13(18):e70400. doi: 10.14814/phy2.70400.
Triple-negative breast cancer (TNBC) predominantly affects young and minority women, with cytotoxic chemotherapy regimens causing severe side effects, including chronic cardiac dysfunction. Obesity worsens TNBC survival. Inositol-requiring enzyme-1 (IRE1), a key arm of the unfolded protein response (UPR), influences tumor progression. Using a TNBC mouse model with control and Western diets, we tested IRE1-targeting antisense morpholino and doxorubicin. Targeting IRE1 alone reduced tumor growth and, combined with doxorubicin, did not interfere with the oncologic efficacy of this drug. We observed that increased activation of caspase-3 was consistently activated by IRE1 in tumors regardless of diet and combination treatment. Furthermore, the blockade of IRE1 mitigated chemotherapy-induced cardiotoxicity by preserving systolic dysfunction, reducing cardiac fibrosis, and preventing cell death. The potential difference in cell death mechanisms observed between the heart and tumors may be associated with different levels of oxidative stress as measured by 4HNE in our in vivo model. Thus, systemic IRE1 suppression protected cardiac tissue while preserving the oncologic efficacy of anthracyclines.
三阴性乳腺癌（TNBC）主要影响年轻女性和少数族裔女性，细胞毒性化疗方案会导致严重的副作用，包括慢性心脏功能障碍。肥胖会恶化TNBC患者的生存率。肌醇需求酶1（IRE1）是未折叠蛋白反应（UPR）的关键分支，影响肿瘤进展。我们使用对照饮食和西式饮食的TNBC小鼠模型，测试了靶向IRE1的反义吗啉代寡核苷酸和阿霉素。单独靶向IRE1可减少肿瘤生长，与阿霉素联合使用时，不会干扰该药物的肿瘤学疗效。我们观察到，无论饮食和联合治疗如何，肿瘤中的IRE1都会持续激活caspase-3。此外，阻断IRE1可通过维持收缩功能障碍、减少心脏纤维化和防止细胞死亡来减轻化疗引起的心脏毒性。在我们的体内模型中，通过4HNE测量，心脏和肿瘤之间观察到的细胞死亡机制的潜在差异可能与不同水平的氧化应激有关。因此，全身性IRE1抑制可保护心脏组织，同时保留蒽环类药物的肿瘤学疗效。
