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

  • Life Sci. 2024 Aug 1:350:122763. doi: 10.1016/j.lfs.2024.122763.
Jing Yu  1 ,  Yongjun Du  1 ,  Chang Liu  2 ,  Yu Xie  1 ,  Mengci Yuan  1 ,  Meihua Shan  3 ,  Ning Li  4 ,  Chang Liu  5 ,  Yue Wang  6 ,  Junfang Qin  7
Affiliations
  • 1. School of Medicine, Nankai University, Tianjin 300071, China.
  • 2. School of Medicine, Nankai University, Tianjin 300071, China. Electronic address: [email protected].
  • 3. Department of Clinical Biochemistry, Army Medical University, Chongqing 400038, China.
  • 4. Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China.
  • 5. School of Medicine, Nankai University, Tianjin 300071, China. Electronic address: [email protected].
  • 6. School of Medicine, Nankai University, Tianjin 300071, China; Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Hospital of Stomatology, Nankai University, Tianjin 300041, China. Electronic address: [email protected].
  • 7. School of Medicine, Nankai University, Tianjin 300071, China. Electronic address: [email protected].
PMID: 38823505 DOI: 10.1016/j.lfs.2024.122763
Abstract

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.

Keywords
Autophagy; Fatty acid oxidation; GPR81; PPARα; Tamoxifen resistance.
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