Background: Not only four but rather seven different human epidermal growth factor receptor related (Her)\r\nreceptor tyrosine kinases (RTKs) have been described to be expressed in a variety of normal and neoplastic tissues:\r\nHer1, Her2, Her3, and additionally four Her4 isoforms have been identified. A differential expression of Her4 isoforms\r\ndoes not, however, play any role in either the molecular diagnostics or treatment decision for breast cancer\r\npatients. The prognostic and predictive impact of Her4 expression in breast cancer is basically unclear.\r\nMethods: We quantified the Her4 variants JM-a/CYT1, JM-a/CYT2, JM-b/CYT1, and JM-b/CYT2 by isoform-specific\r\npolymerase chain reaction (qPCR) in (i) triple-negative, (ii) Her2 positive breast cancer tissues and (iii) in benign\r\nbreast tissues.\r\nResults: In all three tissue collectives we never found the JM-b/CYT1 or the JM-b/CYT2 isoform expressed. In\r\ncontrast, the two JM-a/CYT1 and JM-a/CYT2 isoforms were always simultaneously expressed but at different ratios.\r\nWe identified a positive prognostic impact on overall survival (OS) in triple-negative and event-free survival (EFS) in\r\nHer2 positive patients. This finding is independent of the absolute JM-a/CYT1 to JM-a/CYT2 expression ratio. In\r\nHer2 positive patients, Her4 expression only has a favorable effect in estrogen-receptor (ER)-positive but not in\r\nER-negative individuals.\r\nConclusion: In summary, JM-a/CYT1 and JM-a/CYT2 but not JM-b isoforms of the Her4 receptor are simultaneously\r\nexpressed in both triple-negative and Her2 positive breast cancer tissues. Although different expression ratios of\r\nthe two JM-a isoforms did not reveal any additional information, Her4 expression basically indicates a prolonged\r\nEFS and OFS. An extended expression analysis that takes all Her receptor homologs, including the Her4 isoforms,\r\ninto account might render more precisely the molecular diagnostics required for the development of optimized\r\ntargeted therapies.
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