Machleidt Anna, Buchholz Stefan, Diermeier-Daucher Simone, Zeman Florian, Ortmann Olaf, Brockhoff Gero
Department of Gynecology and Obstetrics, University Medical Center, Caritas Hospital St, Josef, University of Regensburg, Landshuter Strasse 65, 93053 Regensburg, Germany.
BMC Cancer. 2013 Sep 24;13:437. doi: 10.1186/1471-2407-13-437.
Not only four but rather seven different human epidermal growth factor receptor related (Her) receptor tyrosine kinases (RTKs) have been described to be expressed in a variety of normal and neoplastic tissues: Her1, Her2, Her3, and additionally four Her4 isoforms have been identified. A differential expression of Her4 isoforms does not, however, play any role in either the molecular diagnostics or treatment decision for breast cancer patients. The prognostic and predictive impact of Her4 expression in breast cancer is basically unclear.
We quantified the Her4 variants JM-a/CYT1, JM-a/CYT2, JM-b/CYT1, and JM-b/CYT2 by isoform-specific polymerase chain reaction (qPCR) in (i) triple-negative, (ii) Her2 positive breast cancer tissues and (iii) in benign breast tissues.
In all three tissue collectives we never found the JM-b/CYT1 or the JM-b/CYT2 isoform expressed. In contrast, the two JM-a/CYT1 and JM-a/CYT2 isoforms were always simultaneously expressed but at different ratios. We identified a positive prognostic impact on overall survival (OS) in triple-negative and event-free survival (EFS) in Her2 positive patients. This finding is independent of the absolute JM-a/CYT1 to JM-a/CYT2 expression ratio. In Her2 positive patients, Her4 expression only has a favorable effect in estrogen-receptor (ER)-positive but not in ER-negative individuals.
In summary, JM-a/CYT1 and JM-a/CYT2 but not JM-b isoforms of the Her4 receptor are simultaneously expressed in both triple-negative and Her2 positive breast cancer tissues. Although different expression ratios of the two JM-a isoforms did not reveal any additional information, Her4 expression basically indicates a prolonged EFS and OFS. An extended expression analysis that takes all Her receptor homologs, including the Her4 isoforms, into account might render more precisely the molecular diagnostics required for the development of optimized targeted therapies.
已发现七种而非四种不同的人类表皮生长因子受体相关（Her）受体酪氨酸激酶（RTK）在多种正常和肿瘤组织中表达：Her1、Her2、Her3，此外还鉴定出四种Her4亚型。然而，Her4亚型的差异表达在乳腺癌患者的分子诊断或治疗决策中均不起任何作用。Her4表达在乳腺癌中的预后和预测影响基本尚不清楚。
我们通过亚型特异性聚合酶链反应（qPCR）对（i）三阴性、（ii）Her2阳性乳腺癌组织及（iii）良性乳腺组织中的Her4变体JM-a/CYT1、JM-a/CYT2、JM-b/CYT1和JM-b/CYT2进行定量分析。
在所有这三种组织样本中，我们从未发现JM-b/CYT1或JM-b/CYT2亚型有表达。相反，两种JM-a/CYT1和JM-a/CYT2亚型总是同时表达，但比例不同。我们发现其对三阴性患者的总生存期（OS）及Her2阳性患者的无事件生存期（EFS）有积极的预后影响。这一发现与JM-a/CYT1至JM-a/CYT2的绝对表达比例无关。在Her2阳性患者中，Her4表达仅对雌激素受体（ER）阳性个体有有利影响，对ER阴性个体则无。
总之，Her4受体的JM-a/CYT1和JM-a/CYT2亚型而非JM-b亚型在三阴性和Her2阳性乳腺癌组织中同时表达。尽管两种JM-a亚型的不同表达比例未揭示任何额外信息，但Her4表达基本表明EFS和OFS延长。将所有Her受体同源物（包括Her4亚型）纳入考虑的扩展表达分析可能会更精确地提供优化靶向治疗所需的分子诊断信息。
