(502a) The Role of Cell Microenvironment Stimuli on IRE1? Activation to Promote DNA Damage Repair and Development of Chemotolerant Breast Cancer Cells

Obesity can exacerbate tumor microenvironment and lead to cellular dysfunction. Obesity is known to be a risk factor for cancer progression and is linked to reduced effectiveness of chemotherapy. With the increasing prevalence of obesity in the US population, we need to better understand how obesity affects chemotherapy. Previously we showed that palmitate (PA), the most common saturated fatty acid in the human body is elevated in obese patients and induces endoplasmic reticulum (ER) stress by promoting the dimerization of inositol-requiring enzyme 1α (IRE1α). More recently, we found that PA promotes cancer progression and metastasis, mediated by IRE1α.

Increasing evidence supports cross-talk between protein homeostasis (ER stress response) and genome integrity (DNA damage response). In agreement with this, we found that PA reduced DNA damage in breast cancer MDA-MB-231 cells treated with a chemotherapeutic agent, etoposide (a potent inducer for DNA double stranded breaks), and that the cellular protection was dependent on IRE1α function. We employed wild-type, IRE1α knockout, and IRE1α mutant MDA-MB-231 cells and demonstrated that the activation of IRE1α by PA contributed to increasing DNA damage repair activity in response to etoposide-induced DNA double stranded breaks. Furthermore, we found that IRE1α plays an important role in regulating H2A.X, a histone involved in DNA damage response.

This research is the first to show that 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.