2. Academic Validation
  3. Low GPR81 in ER+ breast cancer cells drives tamoxifen resistance through inducing PPARα-mediated fatty acid oxidation

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

Affiliations

  • 1 School of Medicine, Nankai University, Tianjin 300071, China.
  • 2 School of Medicine, Nankai University, Tianjin 300071, China. Electronic address: 1911095@mail.nankai.edu.cn.
  • 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: changliu@nankai.edu.cn.
  • 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: wangyue@nankai.edu.cn.
  • 7 School of Medicine, Nankai University, Tianjin 300071, China. Electronic address: qjf@nankai.edu.cn.
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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