Characterisation of HER heterodimers in breast cancer using in situ proximity ligation assay
Characterisation of HER heterodimers in breast cancer using in situ proximity ligation assay
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DOI：
10.1007/s10549-014-2871-4
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发表时间：
2014-04-01
影响因子：
3.8
通讯作者：
Green, Andrew R.
中科院分区：
文献类型：
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作者：
Barros, Fabricio F. T.;Abdel-Fatah, Tarek M. A.;Green, Andrew R.
HER2在乳腺癌进展中发挥重要作用，并提供预测和预后信息。HER2受体家族成员通过二聚化发挥作用，从而影响细胞功能、生长和分化；然而，它们在乳腺癌发展中的价值仍有待确定。本研究旨在探讨HER2异源二聚体与曲妥珠单抗治疗和治疗病例中乳腺癌特征的关系。在组织微阵列（TMA）格式制备的两个乳腺癌系列中，评估了HER2蛋白（IHC）、HER2基因（显色ISH）和HER2异源二聚化状态[显色原位邻近结扎法（PLA）]。每个HER2异源二聚体检测到一系列信号/细胞（0-34.6个信号/细胞）。绝大多数HER2异源二聚体病例显示HER2基因扩增和/或蛋白表达。HER2二聚化与HER3和HER4及其蛋白表达水平之间存在关联，但在HER1 （EGFR）中未发现这种关联。在HER2+的病例中，分别有74%、66%和58%的患者表现出EGFR、HER3和HER4的异源二聚体。51%的HER2+肿瘤表达所有三种异源二聚体，而23%的病例未显示三种异源二聚体中的任何一种表达。HER2+肿瘤中HER2异源二聚体的存在和水平与激素受体表达呈负相关。表现出高水平HER2异源二聚体的肿瘤表现出侵袭性的临床病理特征和不良的预后。在HER2+病例中，与EGFR和HER3的二聚化与侵袭性特征相关，而与HER4的二聚化不相关。HER2异源二聚体与接受曲妥珠单抗或未接受曲妥珠单抗治疗的HER2阳性乳腺癌患者的乳腺癌特异性生存或复发之间没有关联。我们的研究结果表明，HER2二聚化是一个复杂的过程，可能是HER2阳性肿瘤生物学异质性的基础，可能确定适合特定靶向治疗的患者，但不能预测接受曲妥珠单抗的患者的预后。PLA被证明是一种有用的工具，用于检测、可视化和定量档案福尔马林固定石蜡包埋组织样品中蛋白质-蛋白质相互作用的频率。
HER2 plays an important role in breast cancer progression and provides predictive and prognostic information. HER2 receptor family members function through dimerisation, which can lead to impact on cell function, growth and differentiation; however, their value in breast cancer development remains to be defined. This study aims to examine the relationships of HER2 heterodimers to breast cancer characteristics in trastuzumab na < ve and treated cases. HER2 protein (IHC), HER2 gene (chromogenic ISH) and HER2 heterodimerisation status [chromogenic in situ proximity ligation assay (PLA)] were assessed in two breast cancer series prepared in tissue microarray (TMA) format. A range of signals/cell for each HER2 heterodimer was detected (0-34.6 signals/cell). The vast majority of cases with HER2 heterodimers showed HER2 gene amplification and/or protein expression. There was an association between HER2 dimerisation with HER3 and HER4 and their protein expression level but no such association was found in with HER1 (EGFR). Of the HER2+ cases, 74, 66, and 58 % showed heterodimers with EGFR, HER3 and HER4, respectively. 51 % of HER2+ tumours expressed all three heterodimers whereas 23 % of the cases did not show expression of any of the three heterodimers. There was an inverse association between the presence and levels of HER2 heterodimers and hormone receptor expression in HER2+ tumours. Tumours exhibiting high levels of HER2 heterodimers demonstrated aggressive clinicopathological features and poor outcome. In the HER2+ cases, dimerisation with EGFR and HER3 but not with HER4 showed an association with aggressive features. There was no association between HER2 heterodimers with patient breast cancer-specific survival or recurrence in HER2+ breast cancer in those patients receiving trastuzumab or not. Our results demonstrate that HER2 dimerisation is a complex process that may underlie the biological heterogeneity of HER2 positive tumours and may identify patients suitable for a specific targeted therapy but does not predict patient outcome for those receiving trastuzumab. PLA proved to be a useful tool for detecting, visualising and quantifying the frequency of protein-protein interactions in archival formalin-fixed paraffin-embedded tissue samples.