Abstract
BackgroundNot 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.MethodsWe 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.ResultsIn 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.ConclusionIn 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.
Highlights
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 four Her4 isoforms have been identified
Her4 isoform expression in Triple-negative breast cancer (TNBC) and Her2 positive patients We found the Her4 juxtamembrane Juxtamembrane splice variant a (JM-a) splice variants expressed at a frequency of 18.4% (14 of 76) in triplenegative and 43% (41 of 96) in Her2 positive breast cancer samples
The retrospective study we present here reveals for the first time a favorable impact of Her4 expression on the overall survival (OS) of TNBC patients
Summary
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: Her, Her, Her, and four Her isoforms have been identified. The prognostic and predictive impact of Her expression in breast cancer is basically unclear The Her (human epidermal growth factor related) receptor tyrosine kinases (RTK) comprise four homologous proteins (Her1-4), which are differentially expressed during development and functional maintenance of the normal mammary gland [1,2,3,4]. The prognostic (and predictive) value of Her receptor expression is uncertain [10,11,12,13,14,15,16] Both a positive and a negative impact of Her (co-)expression has been reported. The prognostic value of isoform-related Her expression in breast cancer is, unknown
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