Muftah Abir A, Aleskandarany Mohammed, Sonbul Sultan N, Nolan Christopher C, Diez Rodriguez Maria, Caldas Carlos, Ellis Ian O, Green Andrew R, Rakha Emad A
Division of Cancer and Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.
Department of Pathology, Faculty of Medicine, University of Benghazi, Benghazi, Libya.
Histopathology. 2017 Feb;70(3):456-465. doi: 10.1111/his.13089. Epub 2016 Nov 28.
Although oestrogen receptor (ER)-negative breast cancers (BCs) do not respond to hormone therapy, the response of ER-positive BCs is reported to be variable, which may suggest a dose-dependent effect. The aim of this study was to assess the pattern of ER expression in BCs at the protein (immunohistochemistry) and transcriptome (microarray-based gene expression) levels.
ER immunohistochemical (IHC) expression was assessed in a large series of BCs, including 3649 core biopsies and 1892 cases prepared as tissue microarrays (TMAs) stained with specific antibodies. ESR1 mRNA expression was assessed in the METABRIC study (1980 cases), by the use of the Linear Models for Microarray Data (limma) software, and the results were compared with protein levels. IHC data confirmed the bimodality of ER expression, with 92.2% and 89.2% of the cases showing completely negative (<1%) or highly positive (≥70%) expression on the cores and TMAs, respectively. Weakly positive cases (1-10%) and intermediately positive (11-69%) cases were infrequent (2.7% and 5.1%, and 1.6% and 9.2%, in cores and TMAs, respectively), and did not show survival difference from ER-negative tumours. When full-face sections of the corresponding excision specimens were immunostained, 47% of the ER-low/intermediate group were deemed to be ER-negative. Transcriptomic data not only showed a significant correlation between ESR1 mRNA and protein expression levels, but also confirmed the bimodality of ER expression at the mRNA level.
Our study provides further evidence that ER expression is bimodal, and that it is observed at both the mRNA and protein levels. The reported poor survival of BC patients with low ER expression in the early clinical trials may be related to the inclusion of ER-negative cases.
尽管雌激素受体（ER）阴性乳腺癌（BC）对激素治疗无反应，但据报道ER阳性BC的反应存在差异，这可能提示存在剂量依赖性效应。本研究的目的是在蛋白质（免疫组织化学）和转录组（基于微阵列的基因表达）水平评估BC中ER表达模式。
在大量BC病例中评估ER免疫组化（IHC）表达，包括3649例芯针活检和1892例制备为组织芯片（TMA）并用特异性抗体染色的病例。在METABRIC研究（1980例）中，使用微阵列数据线性模型（limma）软件评估ESR1 mRNA表达，并将结果与蛋白质水平进行比较。IHC数据证实了ER表达的双峰性，芯针活检和TMA上分别有92.2%和89.2%的病例显示完全阴性（<1%）或高度阳性（≥70%）表达。弱阳性病例（1 - 10%）和中度阳性（11 - 69%）病例较少见（芯针活检和TMA中分别为2.7%和5.1%，以及1.6%和9.2%），且与ER阴性肿瘤相比无生存差异。当对相应切除标本的全层切片进行免疫染色时，47%的ER低/中度组被认为是ER阴性。转录组数据不仅显示ESR1 mRNA与蛋白质表达水平之间存在显著相关性，还证实了mRNA水平上ER表达的双峰性。
我们的研究提供了进一步证据，表明ER表达是双峰性的，且在mRNA和蛋白质水平均有观察到。早期临床试验中报道的ER低表达BC患者生存较差可能与纳入ER阴性病例有关。
