# CD36 enhances sensitivity of triple negative breast cancer cells to palmitate-induced ferroptosis

## TL;DR

This study shows that CD36 increases the sensitivity of aggressive breast cancer cells to a type of cell death called ferroptosis when exposed to a fatty acid called palmitate.

## Contribution

The study reveals a novel role of CD36 in promoting ferroptosis in triple negative breast cancer via palmitate-induced mechanisms.

## Key findings

- CD36 overexpression increases lipid uptake and ferroptosis markers in triple negative breast cancer cells.
- Palmitate exposure alters expression of ferroptosis-related genes in TNBC but not in estrogen receptor positive breast cancer.
- Higher CD36 expression correlates with a TNBC subtype more sensitive to ferroptosis.

## Abstract

Ferroptosis is a newly identified programmed cell death induced by iron-driven lipid peroxidation and implicated as a potential approach for tumor treatment. 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.