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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296966 | GEO | 2025/12/10

REPOSITORIES: GEO

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Project description:Background: Prolonged exposure to elevated free fatty acids induces β-cell failure (lipotoxicity) and contributes to the pathogenesis of type 2 diabetes. In vitro exposure of β-cells to the saturated free fatty acid palmitate is a valuable model of lipotoxicity, reproducing features of β-cell failure observed in type 2 diabetes. In order to map the β-cell response to lipotoxicity, we combined RNA-sequencing of palmitate-treated human islets with iTRAQ proteomics of insulin-secreting INS-1E cells following a time course exposure to palmitate. Results: Crossing transcriptome and proteome of palmitate-treated β-cells revealed 85 upregulated and 122 downregulated genes at both transcript and protein level. Pathway analysis identified lipid metabolism, oxidative stress, amino-acid metabolism and cell cycle pathways among the most enriched palmitate-modified pathways. Palmitate induced gene expression changes compatible with increased free fatty acid mitochondrial import and β-oxidation, decreased lipogenesis and modified cholesterol transport. Palmitate modified genes regulating endoplasmic reticulum (ER) function, ER-to-Golgi transport and ER stress pathways. Furthermore, palmitate modulated cAMP/protein kinase A (PKA) signaling, inhibiting expression of PKA anchoring proteins and downregulating the GLP-1 receptor. SLC7 family amino-acid transporters were upregulated in response to palmitate but this induction did not contribute to β-cell demise. To unravel critical mediators of lipotoxicity upstream of the palmitate-modified genes, we identified overrepresented transcription factor binding sites and performed network inference analysis. These identified LXR, PPARα, FOXO1 and BACH1 as key transcription factors orchestrating the metabolic and oxidative stress responses to palmitate. Conclusions: This is the first study to combine transcriptomic and sensitive time course proteomic profiling of palmitate-exposed β-cells. Our results provide comprehensive insight into gene and protein expression changes, corroborating and expanding beyond previous findings. The identification of critical drivers and pathways of the β-cell lipotoxic response points to novel therapeutic targets for type 2 diabetes.

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

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