(526b) The Effects of Palmitate-Induced IRE1? Activation in DNA Double Strand Break Repair and the Development of Chemotolerant Breast Cancer Cells

Obesity is linked to increased risk of breast cancer, cancer progression, and chemtolerance. Although obesity is associated with reduced responses to chemotherapy, it is unclear how obesity worsens treatment outcomes and contributes to poorer survival rates in breast cancer patients. Given the increasing prevalence of obesity in the US population, understanding how obesity affects chemotherapeutic treatment is critical. Palmitate (PA), the most common saturated fatty acid in the human body, concentration is elevated in the blood of obese patients. Our laboratory previously showed that PA activates a pro-survival mechanism that promotes cancer progression and metastasis, mediated by an endoplasmic reticulum (ER) stress sensor protein - inositol-requiring enzyme 1α (IRE1α). There is evidence that supports the involvement of IRE1α in the DNA damage response. Previously our group showed that PA promotes the dimerization and activation of IRE1α. More recently, we found that PA reduced DNA double stranded breaks in breast cancer cells treated with a chemotherapy drug. Our results are the first to suggest a role of PA in DNA damage response mediated by IRE1α. Thus, we investigated the effects of PA on the DNA damage response of breast cancer MDA-MB-231 cells treated with a chemotherapeutic agent, etoposide (a potent inducer for DNA double stranded breaks). We hypothesized that the protective effect of PA on etoposide-treated MDA-MB-231 cells would depend on IRE1α. To test this hypothesis, we employed wild-type, IRE1α knockout, and IRE1α mutant MDA-MB-231 cells. Our results demonstrated that the activation of IRE1α by PA contributed to increasing DNA damage repair activity in response to etoposide-induced DNA double stranded breaks. This research is the first to uncover how PA contributes to DNA damage repair mediated through IRE1α, enhancing the survival of cancer cells treated with anti-cancer drugs. This is significant because (i) PA and ER stress are involved in numerous aging diseases, and (ii) a clear understanding of the molecular mechanism by which PA contributes to cancer cell survival will support the development of novel therapeutics for treating chemotolerance, which is more frequently detected in obese individuals.