Dietary influences on chemotherapy sensitivity and cardiotoxicity modulated by IRE1 targeting in triple-negative breast cancer in female mice

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.