Low GPR81 in ER breast cancer cells drives tamoxifen resistance through inducing PPARα-mediated fatty acid oxidation.

Aims: The intricate molecular mechanisms underlying estrogen receptor-positive (ER) breast carcinogenesis and resistance to endocrine therapy remain elusive. In this study, we elucidate the pivotal role of GPR81, a G protein-coupled receptor, in ER breast cancer (BC) by demonstrating low expression of GPR81 in tamoxifen (TAM)-resistant ER BC cell lines and tumor samples, along with the underlying molecular mechanisms.

Main Methods: Fatty acid oxidation (FAO) levels and lipid accumulation were explored using MDA and FAβO assay, BODIPY 493/503 staining, and Lipid TOX staining. Autophagy levels were assayed using CYTO-ID detection and Western blotting. The impact of GPR81 on TAM resistance in BC was investigated through CCK8 assay, colony formation assay and a xenograft mice model.

Results: Aberrantly low GPR81 expression in TAM-resistant BC cells disrupts the Rap1 pathway, leading to the upregulation of PPARα and CPT1. This elevation in PPARα/CPT1 enhances FAO, impedes lipid accumulation and lipid droplet (LD) formation, and subsequently inhibits cell autophagy, ultimately promoting TAM-resistant BC cell growth. Moreover, targeting GPR81 and FAO emerges as a promising therapeutic strategy, as the GPR81 agonist and the CPT1 inhibitor etomoxir effectively inhibit ER BC cell and tumor growth in vivo, re-sensitizing TAM-resistant ER cells to TAM treatment.

Conclusion: Our data highlight the critical and functionally significant role of GPR81 in promoting ER breast tumorigenesis and resistance to endocrine therapy. GPR81 and FAO levels show potential as diagnostic biomarkers and therapeutic targets in clinical settings for TAM-resistant ER BC.