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Cytoplasmic ERα and NFκB Promote Cell Survival in Mouse Mammary Cancer Cell Lines.
Hormones and Cancer Pub Date : 2020-02-01 , DOI: 10.1007/s12672-020-00378-2
Emily Smart 1 , Luis H Alejo 1 , Jonna Frasor 1
Affiliation  

There is a desperate need in the field for mouse mammary tumors and cell lines that faithfully mimic estrogen receptor (ER) expression and activity found in human breast cancers. We found that several mouse mammary cancer cell lines express ER but fail to demonstrate classical estrogen-driven proliferation or transcriptional activity. We investigated whether these cell lines may be used to model tamoxifen resistance by using small molecule inhibitors to signaling pathways known to contribute to resistance. We found that the combination of NFκB inhibition and ER antagonists significantly reduced cell proliferation in vitro, as well as growth of syngeneic tumors. Surprisingly, we found that ER was localized to the cytoplasm, regardless of any type of treatment. Based on this, we probed extra-nuclear functions of ER and found that co-inhibition of ER and NFκB led to an increase in oxidative stress and apoptosis. Together, these findings suggest that cytoplasmic ER and NFκB may play redundant roles in protecting mammary cancer cells from oxidative stress and cell death. Although this study has not identified a mouse model with classical ER activity, cytoplasmic ER has been described in a small subset of human breast tumors, suggesting that these findings may be relevant for some breast cancer patients.

中文翻译:

细胞质ERα和NFκB促进小鼠乳腺癌细胞系中的细胞存活。

在该领域中迫切需要忠实模拟人类乳腺癌中发现的雌激素受体(ER)表达和活性的小鼠乳腺肿瘤和细胞系。我们发现几种小鼠乳癌细胞系表达ER,但未能证明经典的雌激素驱动的增殖或转录活性。我们调查了这些细胞系是否可通过使用小分子抑制剂向已知有助于抵抗的信号传导途径来模拟他莫昔芬的抵抗。我们发现,NFκB抑制物和ER拮抗剂的组合可显着降低体外细胞增殖以及同基因肿瘤的生长。出人意料的是,我们发现ER定位于细胞质,无论采用哪种治疗方法。基于此,我们探究了ER的核外功能,发现ER和NFκB的共同抑制导致氧化应激和细胞凋亡的增加。总之,这些发现表明细胞质ER和NFκB可能在保护乳癌细胞免受氧化应激和细胞死亡方面起着多余的作用。尽管该研究尚未鉴定出具有经典ER活性的小鼠模型,但已经在人类乳腺肿瘤的一小部分中描述了细胞质ER,这表明这些发现可能与某些乳腺癌患者有关。
更新日期:2020-02-01
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