Reversal of endocrine resistance via N6AMT1-NEDD4L pathway-mediated p110α degradation.

Autor: Ji L; Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China., Chen J; Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China., He L; Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China., Zhang F; Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China., Deng Z; Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China., Lin J; Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China., Qi Z; Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China., Luo X; Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China., Giuliano AE; Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Cui X; Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Lin SL; Department of Cell Biology, Shantou University Medical College, Shantou, Guangdong, China., Cui Y; Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China. ykcui@stu.edu.cn.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2024 Dec 02. Date of Electronic Publication: 2024 Dec 02.
DOI: 10.1038/s41388-024-03238-3
Abstrakt: Approximately 70% of breast cancer (BC) cases are luminal-type (estrogen receptor-positive, ER+), suitable for endocrine therapy with tamoxifen as the most commonly used drug. However, about 30% of these patients develop tamoxifen resistance due to various mechanisms, primarily involving PI3K pathway activation through mutations or unknown pathways. Here, we discover, via bioinformatics analysis and clinical samples, that N6 adenine-specific DNA methyltransferase 1 (N6AMT1) is highly expressed in luminal breast cancer but downregulated in tamoxifen-resistant (TamR) BC cells. ChIP-qPCR and luciferase reporter assays showed that FOXA1 binds to the N6AMT1 promoter and enhances its transcription. In TamR models, FOXA1 and N6AMT1 are downregulated, increasing p110α protein levels (but not mRNA), phospho-AKT levels, and tamoxifen resistance. In vivo, N6AMT1 overexpression enhanced tamoxifen sensitivity, while knockdown reduced it; this sensitivity could be restored with the p110α inhibitor A66. Clinically, decreased N6AMT1 expression correlates with poor prognosis in luminal BC patients. In TamR BC organoids, combining tamoxifen with A66 further reduced growth compared to either treatment alone. Mechanistically, increased p110α levels result from inhibited degradation by E3 ubiquitin ligase NEDD4L. These findings suggest N6AMT1 as a potential luminal breast cancer biomarker and highlight the N6AMT1-p110α pathway as a therapeutic target to sensitize cells to tamoxifen.
Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All methods in this study were performed in accordance with relevant guidelines and regulations. Ethical approval was obtained from the Ethics Committee of Cancer Hospital of Shantou University Medical College (Approval No. 2022-022) and the Laboratory Animal Ethics Committee of Shantou University Medical College (Approval No. 2022-077). Informed consent was obtained from all participants involved in the study.
(© 2024. The Author(s).)
Databáze: MEDLINE
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