对孕酮反应能力正常或降低的乳腺癌细胞池的分子特征:一项基于RNA-seq的研究

IF 3.6 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal, genetic engineering & biotechnology Pub Date : 2023-08-08 DOI:10.1186/s43141-023-00541-6
Mariana Bustamante Eduardo, Irene Keller, Nathalie Schuster, Stefan Aebi, Rolf Jaggi
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摘要

背景:雌激素受体α (ERα)阳性乳腺癌患者中约有三分之一的肿瘤为孕激素受体(PR)阴性。PR是乳腺癌预后的重要因素。er α-阳性/ pr -阴性肿瘤患者的无病生存期和总生存期较er α-阳性/ pr -阳性肿瘤患者短。新的证据表明,孕酮(P4)对er α阳性乳腺癌细胞具有抗增殖作用。然而,PR在乳腺癌中的作用尚不清楚。方法:利用CRISPR/Cas9系统对er α阳性/PR阳性T-47D细胞的PR基因(PGR)进行破坏。与对照T-47D细胞相比,P4介导的作用被抑制或阻断,导致细胞池的pr降低。我们分析了PR-low和对照T-47D细胞在缺乏激素、P4单独或P4与雌二醇(E2)联合治疗时的基因表达谱。通过RNA-seq和基因本体(GO)富集分析,对实验组之间的差异表达基因(DE)进行了表征。结果:未经PR-low处理的T-47D细胞与未经PR-low处理的T-47D细胞的整体基因表达模式非常相似。在P4或P4 + E2刺激下,对照T-47D细胞中有6000多个基因被DE。当PR-low池受到相同的激素治疗时,上调或下调要么被阻断/缺失,要么持续降低。我们确定了3000多个基因在激素处理的PR-low细胞和对照T-47D细胞之间是DE。氧化石墨烯分析揭示了七个显著富集的受PR影响的生物过程,并与G蛋白偶联受体(GPCR)途径相关,这些途径被描述为支持乳腺癌细胞的生长、侵袭和转移。结论:本研究为PR在er α阳性/PR阳性乳腺癌细胞中的复杂作用提供了新的见解。许多受PR影响的基因是肿瘤发生的中心生物学过程的一部分。
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Molecular characterization of breast cancer cell pools with normal or reduced ability to respond to progesterone: a study based on RNA-seq.

Background: About one-third of patients with estrogen receptor alpha (ERα)-positive breast cancer have tumors which are progesterone receptor (PR) negative. PR is an important prognostic factor in breast cancer. Patients with ERα-positive/PR-negative tumors have shorter disease-free and overall survival than patients with ERα-positive/PR-positive tumors. New evidence has shown that progesterone (P4) has an anti-proliferative effect in ERα-positive breast cancer cells. However, the role of PR in breast cancer is only poorly understood.

Methods: We disrupted the PR gene (PGR) in ERα-positive/PR-positive T-47D cells using the CRISPR/Cas9 system. This resulted in cell pools we termed PR-low as P4 mediated effects were inhibited or blocked compared to control T-47D cells. We analyzed the gene expression profiles of PR-low and control T-47D cells in the absence of hormone and upon treatment with P4 alone or P4 together with estradiol (E2). Differentially expressed (DE) genes between experimental groups were characterized based on RNA-seq and Gene Ontology (GO) enrichment analyses.

Results: The overall gene expression pattern was very similar between untreated PR-low and untreated control T-47D cells. More than 6000 genes were DE in control T-47D cells upon stimulation with P4 or P4 plus E2. When PR-low pools were subjected to the same hormonal treatment, up- or downregulation was either blocked/absent or consistently lower. We identified more than 3000 genes that were DE between hormone-treated PR-low and control T-47D cells. GO analysis revealed seven significantly enriched biological processes affected by PR and associated with G protein-coupled receptor (GPCR) pathways which have been described to support growth, invasiveness, and metastasis in breast cancer cells.

Conclusions: The present study provides new insights into the complex role of PR in ERα-positive/PR-positive breast cancer cells. Many of the genes affected by PR are part of central biological processes of tumorigenesis.

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