Effect of palmitate on breast cancer cells according to CD36 expression

Breast tumors develop in a complex microenvironment whose main component is adipose tissue and gain aggressiveness through increased fatty acid uptake. Here, we demonstrated that palmitic acid (PA) induced ferroptosis in triple negative breast cancers (TNBC). We found that PA increases the protein expression levels of the long-chain fatty acid transporter CD36 leading to increased lipid uptake. Mechanistically, overexpression of CD36 increases lipid peroxidation, mitochondrial ROS production, the labile iron pool and especially Fe2+ content. Additionally, we found increased expression of ferroptotic target genes (HMOX1, ACSL1, SAT1) and decreased of anti-ferroptotic genes (GPX4 and FSP1) in TNBC following PA exposure. Overexpression of CD36 did not induce ferroptosis in estrogen receptor positive breast cancer. Clinically, higher CD36 expression correlated with the luminal androgen receptor (LAR) subtype of TNBC, known to exhibit a higher sensitivity to ferroptosis. Altogether, these data provide evidence for an essential role of the CD36 protein in the ferroptotic process induced by the saturated fatty acid PA, opening potential new therapeutic approaches promoting ferroptosis in the most aggressive breast cancers. Overall design: RNA-seq profiling of wildtype MCF-7 and SUM-159 and their CD36-overexpressed derivatives (MCF-7-CD36 and SUM-159-CD36) treated or not with palmitate.