Androgen receptors promote mitochondrial oxidative phosphorylation, carnitine metabolism, and resistance to palmitate lipotoxicity in ER-mutant breast cancer.

The effect of androgen receptor (AR) in ER+ breast cancer remains controversial. We find that AR promotes tumor cell growth, oxidative phosphorylation, and fatty acid oxidation under conditions mimicking long-term aromatase inhibition. AR also promotes expression of the mitochondrial and peroxisomal acylcarnitine synthesis enzyme CRAT. AR inhibition decreases CRAT expression and CRAT knockdown is sufficient to inhibit OXPHOS. AR inhibition does not elicit a broad anti-OXPHOS transcriptomic signature, but does affect the expression of a few key metabolic enzymes. AR antagonism also induces a metabolomic signature consistent with severe OXPHOS dysfunction. This work identifies AR as a regulator of CRAT and OXPHOS in ER+ breast cancer. Overall design: To identify how AR antagonism affects OXPHOS in ER-mutant breast cancer, we performed bulk mRNA sequencing on Y537S ER-mutant CRISPR knock-in breast cancer cells treated with DMSO or 30 uM Enzalutamide for 96 hours.