Muthukaruppan Anita, Lasham Annette, Woad Kathryn J, Black Michael A, Blenkiron Cherie, Miller Lance D, Harris Gavin, McCarthy Nicole, Findlay Michael P, Shelling Andrew N, Print Cristin G
Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Clin Breast Cancer. 2017 Apr;17(2):139-153. doi: 10.1016/j.clbc.2016.09.001. Epub 2016 Sep 13.
Molecular markers have transformed our understanding of the heterogeneity of breast cancer and have allowed the identification of genomic profiles of estrogen receptor (ER)-α signaling. However, our understanding of the transcriptional profiles of ER signaling remains inadequate. Therefore, we sought to identify the genomic indicators of ER pathway activity that could supplement traditional immunohistochemical (IHC) assessments of ER status to better understand ER signaling in the breast tumors of individual patients.
We reduced ESR1 (gene encoding the ER-α protein) mRNA levels using small interfering RNA in ER MCF7 breast cancer cells and assayed for transcriptional changes using Affymetrix HG U133 Plus 2.0 arrays. We also compared 1034 ER and ER breast tumors from publicly available microarray data. The principal components of ER activity generated from these analyses and from other published estrogen signatures were compared with ESR1 expression, ER-α IHC, and patient survival.
Genes differentially expressed in both analyses were associated with ER-α IHC and ESR1 mRNA expression. They were also significantly enriched for estrogen-driven molecular pathways associated with ESR1, cyclin D1 (CCND1), MYC (v-myc avian myelocytomatosis viral oncogene homolog), and NFKB (nuclear factor kappa B). Despite their differing constituent genes, the principal components generated from these new analyses and from previously published ER-associated gene lists were all associated with each other and with the survival of patients with breast cancer treated with endocrine therapies.
A biomarker of ER-α pathway activity, generated using ESR1-responsive mRNAs in MCF7 cells, when used alongside ER-α IHC and ESR1 mRNA expression, could provide a method for further stratification of patients and add insight into ER pathway activity in these patients.
分子标志物改变了我们对乳腺癌异质性的理解，并使得雌激素受体（ER）-α信号通路的基因组图谱得以识别。然而，我们对ER信号通路转录图谱的理解仍然不足。因此，我们试图识别ER通路活性的基因组指标，以补充传统的免疫组织化学（IHC）对ER状态的评估，从而更好地理解个体患者乳腺肿瘤中的ER信号通路。
我们使用小干扰RNA降低ER MCF7乳腺癌细胞中ESR1（编码ER-α蛋白的基因）的mRNA水平，并使用Affymetrix HG U133 Plus 2.0芯片检测转录变化。我们还比较了来自公开可用微阵列数据的1034例ER阳性和ER阴性乳腺肿瘤。将这些分析以及其他已发表的雌激素特征所产生的ER活性主成分与ESR1表达、ER-α IHC和患者生存率进行比较。
在两项分析中差异表达的基因与ER-α IHC和ESR1 mRNA表达相关。它们还显著富集了与ESR1、细胞周期蛋白D1（CCND1）、MYC（v-myc禽骨髓细胞瘤病毒癌基因同源物）和NFKB（核因子κB）相关的雌激素驱动分子通路。尽管它们的组成基因不同，但这些新分析以及先前发表的ER相关基因列表所产生的主成分彼此相关，且与接受内分泌治疗的乳腺癌患者的生存率相关。
使用MCF7细胞中ESR1反应性mRNA生成的ER-α通路活性生物标志物，与ER-α IHC和ESR1 mRNA表达一起使用时，可以为进一步对患者进行分层提供一种方法，并深入了解这些患者的ER通路活性。
