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Targeting c-Jun inhibits fatty acid oxidation to overcome tamoxifen resistance in estrogen receptor-positive breast cancer.

ABSTRACT: Tamoxifen-based endocrine therapy remains a major adjuvant therapy for estrogen receptor (ER)-positive breast cancer (BC). However, many patients develop tamoxifen resistance, which results in recurrence and poor prognosis. Herein, we show that fatty acid oxidation (FAO) was activated in tamoxifen-resistant (TamR) ER-positive BC cells by performing bioinformatic and functional studies. We also reveal that CPT1A, the rate-limiting enzyme of FAO, was significantly overexpressed and that its enzymatic activity was enhanced in TamR cells. Mechanistically, the transcription factor c-Jun was activated by JNK kinase-mediated phosphorylation. Activated c-Jun bound to the TRE motif in the CPT1A promoter to drive CPT1A transcription and recruited CBP/P300 to chromatin, catalysing histone H3K27 acetylation to increase chromatin accessibility, which ensured more effective transcription of CPT1A and an increase in the FAO rate, eliminating the cytotoxic effects of tamoxifen in ER-positive BC cells. Pharmacologically, inhibiting CPT1A enzymatic activity with the CPT1 inhibitor etomoxir or blocking c-Jun phosphorylation with a JNK inhibitor restored the tamoxifen sensitivity of TamR cells. Clinically, high levels of phosphorylated c-Jun and CPT1A were observed in ER-positive BC tissues in patients with recurrence after tamoxifen therapy and were associated with poor survival. These results indicate that the assessment and targeting of the JNK/c-Jun-CPT1A-FAO axis will provide promising insights for clinical management, increased tamoxifen responses and improved outcomes for ER-positive BC patients.

SUBMITTER: Jiang C

PROVIDER: S-EPMC10558541 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Targeting c-Jun inhibits fatty acid oxidation to overcome tamoxifen resistance in estrogen receptor-positive breast cancer.

Jiang Cen C Zhu Youzhi Y Chen Huaying H Lin Junyu J Xie Ruiwang R Li Weiwei W Xue Jiajie J Chen Ling L Chen Xiangjin X Xu Sunwang S

Cell death & disease 20231006 10

Tamoxifen-based endocrine therapy remains a major adjuvant therapy for estrogen receptor (ER)-positive breast cancer (BC). However, many patients develop tamoxifen resistance, which results in recurrence and poor prognosis. Herein, we show that fatty acid oxidation (FAO) was activated in tamoxifen-resistant (TamR) ER-positive BC cells by performing bioinformatic and functional studies. We also reveal that CPT1A, the rate-limiting enzyme of FAO, was significantly overexpressed and that its enzyma ...[more]

PMID: 37803002

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Targeting c-Jun inhibits fatty acid oxidation to overcome tamoxifen resistance in estrogen receptor-positive breast cancer.

Publications

Targeting c-Jun inhibits fatty acid oxidation to overcome tamoxifen resistance in estrogen receptor-positive breast cancer.

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