原发性乳腺癌中 HER3 表达及其降解调节因子 NEDD4-1 和 NRDP1 的临床病理和预后相关性。

Clinicopathological and prognostic correlations of HER3 expression and its degradation regulators, NEDD4-1 and NRDP1, in primary breast cancer.

机构信息

BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Arvo Ylpön katu 34, 33520, Tampere, Finland.

Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland.

出版信息

BMC Cancer. 2018 Oct 26;18(1):1045. doi: 10.1186/s12885-018-4917-1.

DOI:10.1186/s12885-018-4917-1

PMID:30367623

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6204010/

Abstract

BACKGROUND

Human epidermal growth factor receptor HER3 (ErbB3), especially in association with its relative HER2 (ErbB2), is known as a key oncogene in breast tumour biology. Nonetheless, the prognostic relevance of HER3 remains controversial. NEDD4-1 and NRDP1 are signalling molecules closely related to the degradation of HER3 via ubiquitination. NEDD4-1 and NRDP1 have been reported to contribute to HER3-mediated signalling by regulating its localization and cell membrane retention. We studied correlations between HER3, NEDD4-1, and NRDP1 protein expression and their association with tumour histopathological characteristics and clinical outcomes.

METHODS

The prevalence of immunohistochemically detectable expression profiles of HER3 (n = 177), NEDD4-1 (n = 145), and NRDP1 (n = 145) proteins was studied in primary breast carcinomas on archival formalin-fixed paraffin-embedded (FFPE) samples. Clinicopathological correlations were determined statistically using Pearson's Chi-Square test. The Kaplan-Meier method, log-rank test (Mantel-Cox), and Cox regression analysis were utilized for survival analysis.

RESULTS

HER3 protein was expressed in breast carcinomas without association with HER2 gene amplification status. Absence or low HER3 expression correlated with clinically aggressive features, such as triple-negative breast cancer (TNBC) phenotype, basal cell origin (cytokeratin 5/14 expression combined with ER negativity), large tumour size, and positive lymph node status. Low total HER3 expression was prognostic for shorter recurrence-free survival time in HER2-amplified breast cancer (p = 0.004, p = 0.020 in univariate and multivariate analyses, respectively). The majority (82.8%) of breast cancers demonstrated NEDD4-1 protein expression - while only a minor proportion (8.3%) of carcinomas expressed NRDP1. NEDD4-1 and NRDP1 expression were not associated with clinical outcomes in HER2-amplified breast cancer, irrespective of adjuvant trastuzumab therapy.

CONCLUSIONS

Low HER3 expression is suggested to be a valuable prognostic biomarker to predict recurrence in HER2-amplified breast cancer. Neither NEDD4-1 nor NRDP1 demonstrated relevance in prognostics or in the subclassification of HER2-amplified breast carcinomas.

摘要

背景

人表皮生长因子受体 HER3（ErbB3），尤其是与相对的 HER2（ErbB2）结合，被认为是乳腺癌肿瘤生物学中的关键癌基因。然而，HER3 的预后相关性仍存在争议。NEDD4-1 和 NRDP1 是与通过泛素化降解 HER3 密切相关的信号分子。据报道，NEDD4-1 和 NRDP1 通过调节其定位和细胞膜保留来促进 HER3 介导的信号转导。我们研究了 HER3、NEDD4-1 和 NRDP1 蛋白表达之间的相关性及其与肿瘤组织病理学特征和临床结果的关系。

方法

在原发性乳腺癌存档福尔马林固定石蜡包埋（FFPE）样本上研究了免疫组化可检测的 HER3（n=177）、NEDD4-1（n=145）和 NRDP1（n=145）蛋白表达谱的流行率。使用 Pearson's Chi-Square 检验进行统计学相关性分析。采用 Kaplan-Meier 法、对数秩检验（Mantel-Cox）和 Cox 回归分析进行生存分析。

结果

HER3 蛋白在乳腺癌中表达，与 HER2 基因扩增状态无关。HER3 表达缺失或低表达与临床侵袭性特征相关，如三阴性乳腺癌（TNBC）表型、基底细胞起源（细胞角蛋白 5/14 表达与 ER 阴性相结合）、肿瘤较大和淋巴结阳性。HER2 扩增乳腺癌中总 HER3 低表达与无复发生存时间较短相关（p=0.004，p=0.020 在单变量和多变量分析中）。大多数（82.8%）乳腺癌表现出 NEDD4-1 蛋白表达-而只有少数（8.3%）癌表达 NRDP1。NEDD4-1 和 NRDP1 的表达与 HER2 扩增乳腺癌的临床结局无关，无论是否接受辅助曲妥珠单抗治疗。