靶向EPAS-1/HIF-2α途径解决腔内A型乳腺癌内分泌抵抗

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2025-05-19 DOI:10.1016/j.tranon.2025.102415

Enzhi Luo, Seongmin Lee, Neeraj manvi agarwal, Junjeong Choi

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引用次数: 0

摘要

背景：他莫昔芬最常被用作A腔乳腺癌的首选治疗药物；然而，三分之一的患者对它有抗药性。大量研究表明，缺氧有助于耐药，并与临床预后不良有关。尽管如此，关于他莫昔芬耐药的关键缺氧介质所知甚少。方法利用公开的转录组学和全外显子组测序数据，对他莫昔芬敏感和耐药的luminal a乳腺癌患者样本进行了全面的多组学分析。EPAS1被确定为与腔腔a乳腺癌内分泌抵抗相关的关键缺氧介质。体外实验包括Western blotting、缺氧检测和CCK8检测，验证EPAS1表达与细胞系他莫昔芬耐药之间的关系。此外，我们测试了EPAS1抑制剂PT2977 （Belzutifan）作为他莫昔芬耐药和对照细胞的潜在治疗效果，随后在他莫昔芬耐药肿瘤的异种移植模型中进行了验证。结果患者和细胞系数据显示，EPAS1在耐他莫昔芬的luminal A乳腺癌中显著上调，这与生存预后差和肿瘤微环境改变有关。对他莫昔芬耐药细胞系的进一步研究证实EPAS1表达水平升高。EPAS1抑制剂PT2977体外治疗可显著降低细胞活力并调节缺氧相关通路，表明其具有潜在的治疗作用。此外，体内研究表明，在实验条件下，PT2977降低了他莫昔芬耐药细胞的生长。结论PT2977通过靶向缺氧基因EPAS1，具有抑制耐他莫昔芬luminal A乳腺癌生长的潜力。然而，尽管PT2977在实验条件下显示出抑制肿瘤生长的有效性，但还需要进一步的研究来评估其在克服激素抵抗中的作用，并探索其在更广泛的临床环境和其他癌症亚型中的治疗适用性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Targeting EPAS-1/HIF-2α Pathway to Address Endocrine Resistance in Luminal A Type Breast Cancer

Background

Tamoxifen is most often used as the first treatment for luminal A breast cancer; however, one-third of the patients are resistant to it. Numerous studies have shown that hypoxia contributes to drug resistance and is related to poor clinical outcomes. Despite this, little is known regarding the key hypoxic mediators involved in tamoxifen resistance.

Methods

We performed a comprehensive multi-omics analysis using publicly available transcriptomics and whole-exome sequencing data from tamoxifen-sensitive and tamoxifen-resistant luminal A breast cancer patient samples. EPAS1 was identified as a key hypoxic mediator linked to endocrine resistance in luminal A breast cancer. In vitro assays, including Western blotting, hypoxia detection assays, and CCK8 assays, were conducted to validate the association between EPAS1 expression and tamoxifen resistance in cell lines. Additionally, we tested the effect of PT2977 (Belzutifan), an EPAS1 inhibitor, as a potential treatment for tamoxifen resistance using tamoxifen-resistant and control cells, followed by validation in xenograft models of tamoxifen-resistant tumours.

Results

Patient and cell line data revealed that EPAS1 is significantly upregulated in tamoxifen-resistant luminal A breast cancer, which is associated with poor survival outcomes and an altered tumour microenvironment. Further investigation using tamoxifen-resistant cell lines confirmed elevated EPAS1 expression levels. In vitro treatment with the EPAS1 inhibitor PT2977 resulted in a significant decrease in cell viability and modulated hypoxia-related pathways, indicating a potential therapeutic effect. Furthermore, in vivo studies showed that PT2977 reduced the growth of tamoxifen-resistant cells under the experimental conditions used.

Conclusion

This study suggests that PT2977, by targeting the hypoxic gene EPAS1, has the potential to inhibit the growth of tamoxifen-resistant luminal A breast cancer. However, while PT2977 demonstrated effectiveness in reducing tumour growth under the experimental conditions used, further studies are necessary to evaluate its role in overcoming hormone resistance and to explore its therapeutic applicability in broader clinical settings and other cancer subtypes.

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.