國家衛生研究院 NHRI:Item 3990099045/16913
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    题名: NUPR1 contributes to endocrine therapy resistance by modulating BIRC5 expression and inducing luminal B-ERBB2+ subtype-like characteristics in estrogen breast cancer cells
    作者: Lee, CH;Lin, YC;Chang, YC;Chen, PC;Lin, KH;Yeh, TM;Leung, EY;Lin, IL;Chen, SH;Cheung, CHA
    贡献者: National Institute of Cancer Research
    摘要: Acquired resistance to endocrine therapy is a major clinical challenge in the treatment of luminal A [estrogen receptor (ER)(+)and/or progesterone receptor (PR)+, human epidermal growth factor receptor 2 (ERBB2/HER2)(-), and low Ki-67] breast cancer. Recently, molecular subtype conversion has been suggested as one of the possible causes of the development of drug-resistant breast cancer. However, the molecular mechanism underlying the molecular subtype conversion and the induction of endocrine therapy resistance in luminal A breast cancer is still incompletely understood. Here, we found that the ER+ MCF7-derived endocrine therapy-resistant MCF7-TamC3 breast cancer cells exhibit increased expression of an intrinsically disordered chromatin protein, NUPR1, compared to the parental luminal-A subtype like MCF7 breast cancer cells. Intriguingly, MCF7-TamC3 cells also exhibit characteristics that resemble the luminal B-ERBB2(+) breast tumor subtype, like the increased expression of ERBB2 and the increased sensitivity to monoclonal ERBB2-targeting antibody Trastuzumab in vitro. Kaplan-Meier analysis of expression cohorts of breast tumors showed that high NUPR1 mRNA expression levels correlate with poor overall and relapse-free survival in both endocrine therapy-treated ER+ and ERBB2-enriched breast cancer patients. Results of the bioinformatics analysis showed that the NUPR1 mRNA expression level is also correlated with the clinical grading of the Tamoxifen-treated ER+ primary breast cancer. The qPCR and the western blot analysis results revealed that NUPR1 positively regulates the expression of the epigenetic regulator HDAC5, the anti-apoptotic molecule BIRC5, and the mitogenic receptor ERBB2 in MCF7-TamC3 and the ERBB2-enriched subtype like SK-BR-3 breast cancer cells. Downregulation of NUPR1 increased the sensitivity to estrogen deprivation in MCF7-TamC3 cells and decreased the viability of SK-BR-3 cells in vitro. These findings indicate that dysregulation of NUPR1 promotes the development of estrogen independence in ER+ breast cancer cells in part through expression regulation of HDAC5, ERBB2, and BIRC5. Targeting NUPR1 or its downstream regulating molecules may offer a potential strategy for overcoming resistance to endocrine therapy in patients with ER+ breast cancer.
    日期: 2025-02-11
    關聯: Journal of Cancer. 2025 Feb 11;16(5):1694-1708.
    Link to: http://dx.doi.org/10.7150/jca.105425
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1837-9664&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001426166600020
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=86000124203
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