ArticleJournal of experimental & clinical cancer research : CR2019
Aberrant fatty acid profile and FFAR4 signaling confer endocrine resistance in breast cancer.
Article in Journal of experimental & clinical cancer research : CR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 25 citations in OpenAlex.
- Phase separation of DDHD2 remodels lipid metabolism to dictate treatment sensitivity in luminal breast cancer.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- GPR40 Attenuates Glioma TMZ-Resistance Through Ferroptosis Inhibition.Neurochemical research · 2026Article
- FFAR4 negatively regulates colorectal cancer growth via blocking oxidative phosphorylation.Journal of translational medicine · 2026Article
- Immune evasion driven by lipid metabolic reprogramming in endocrine-resistant HRFrontiers in immunology · 2026Review
- Review
- A lipid metabolism-related gene signature predicts prognosis after tamoxifen treatment in ER + breast cancer and reflects tumor microenvironment heterogeneity through single-cell analysis.BMC medical genomics · 2025Article
- Primary cilia and cancer: a tale of many faces.Oncogene · 2025Review
- Combining fecal microbiome and metabolomics reveals diagnostic biomarkers for esophageal squamous cell carcinoma.Microbiology spectrum · 2024Article
- Reprogramming of Lipid Metabolism Mediates Crosstalk, Remodeling, and Intervention of Microenvironment Components in Breast Cancer.International journal of biological sciences · 2024Review
- Comparative metabolomics of MCF-7 and MCF-7/TAMR identifies potential metabolic pathways in tamoxifen resistant breast cancer cells.American journal of translational research · 2024Article
- Dysregulation of Fatty Acid Metabolism in Breast Cancer and Its Targeted Therapy.Breast cancer (Dove Medical Press) · 2024Review
- The novel epithelial-mesenchymal transition-related proteins and their therapeutic targets in cholangiocarcinoma: a narrative review.Journal of gastrointestinal oncology · 2023Review
- CRISPR-Cas9 screen reveals a role of purine synthesis for estrogen receptor α activity and tamoxifen resistance of breast cancer cells.Science advances · 2023Article
- Obesity and endocrine therapy resistance in breast cancer: Mechanistic insights and perspectives.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2022Review
- Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies.Journal of molecular medicine (Berlin, Germany) · 2021Review
- GPR120/FFAR4 Pharmacology: Focus on Agonists in Type 2 Diabetes Mellitus Drug Discovery.Journal of medicinal chemistry · 2021Article
- Identifying Dendritic Cell-Related Genes Through a Co-Expression Network to Construct a 12-Gene Risk-Scoring Model for Predicting Hepatocellular Carcinoma Prognosis.Frontiers in molecular biosciences · 2021Article
- Functional genetic variant of HSD17B12 in the fatty acid biosynthesis pathway predicts the outcome of colorectal cancer.Journal of cellular and molecular medicine · 2020Article
- The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase.Theranostics · 2020Article
- USP5 Promotes Metastasis in Non-Small Cell Lung Cancer by Inducing Epithelial-Mesenchymal TransitionFrontiers in pharmacology · 2020Article
Corrections and comments
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Authors and funding
17 authors at 7 institutions in 1 country.
Funding
Abstract
backgroundEvidence suggests that fatty acid receptor FFAR4 plays a tumor-promoting role in adipose tissue-adjacent malignancies, but its clinical relevance remains unexplored. Here, we investigated the clinical significance and underlying mechanisms of FFAR4 in hormone receptor-positive breast cancer (HRPBC).
methodsFFAR4 expression was assessed by immunohistochemistry in an exploration cohort of 307 breast cancer cases collected from two independent institutes. Two public breast cancer microarray datasets served as validation cohorts. Gas chromatography-mass spectrometry was employed to identify FFAR4 ligands in normal and cancerous breast tissues. Survival analyses were performed in all cohorts and designated molecular subgroups. Mechanistic studies were performed in vitro in hormone receptor-positive breast cancer cell lines MCF-7 and T-47D.
resultsAberrant FFAR4 expression and endogenous FFAR4 ligands were identified in breast cancer tissues, five FFAR4 ligands showed significantly elevated proportions in cancerous versus normal tissues. In the exploration cohort, FFAR4 was demonstrated as an independent prognostic factor for recurrences (HR: 2.183, 95% CI: 1.360-3.504, P = 0.001) and breast cancer-specific deaths (HR: 2.102, 95% CI: 1.173-3.766, P = 0.013) in HRPBC cases. In contrast, FFAR4 expression was not associated with prognosis in hormone receptor-negative cases. In the validation cohorts, FFAR4 mRNA levels were also observed to be associated with disease recurrence in estrogen receptor-positive cases, but not so in estrogen receptor-negative cases. FFAR4 activation by endogenous ligands and a synthetic ligand TUG891 significantly dampened tamoxifen's efficacy on HRPBC cells, whereas FFAR4 knockdown or antagonist AH7614 abrogated this effect. Furthermore, FFAR4-induced tamoxifen resistance was dependent on ERK and AKT pathways in HRPBC.
conclusionsOur results establish a novel role of FFAR4 and its ligands in the complicated interactions between tissue lipid profile and cancer biology. FFAR4 signaling confers tamoxifen resistance in HRPBC cell line and FFAR4 expression can serve as a prognostic biomarker for tamoxifen-treated HRPBC patients. FFAR4 may serve as a potential target for anti-breast cancer therapies, especially in endocrine resistant cases.
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