The prognostic value of Her4 receptor isoform expression in triple-negative and Her2 positive breast cancer patients

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.

Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

“…In addition, studies have shown that cytoplasmic HER4 is linked with improved survival of breast cancer patients [12, 47]. In our cohort study, we also demonstrated a similar pattern that high level of cytoplasmic HER4 had a better prognosis in HER2 positive breast cancer patients.…”

“…A recent study of HER4 isoform expression in breast cancer demonstrated a correlation between JM-a isoforms (CYT1 and CYT2) with longer patients' survival [12]. In addition, studies have shown that cytoplasmic HER4 is linked with improved survival of breast cancer patients [12, 47].…”

“…In addition, positive HER4 expression was shown to be associated with an increased survival rate of breast cancer patients [11]. A recent study conducted among HER2 positive breast cancer patients demonstrated that HER4 is predictive of longer event-free survival (EFS) in patients with ER positive tumours [12]. That study is in agreement with previous reports that linked high HER4 expression with low tumour grade, low proliferation rate and positive score for ER and PR in breast cancer [13-15].…”

HER4 isoform CYT2 and its ligand NRG1III are expressed at high levels in human colorectal cancer

“…There are potentially oncogenic ERBB4 mutations in non-small cell lung cancer (9), and it has been reported that HER4 is overexpressed in human colon cancer and enhances cellular transformation (10). In addition, HER4 promotes breast cancer cell proliferation, mediates acquired resistance to ERBB2 inhibitors and may serve as a prognostic marker in patients with breast cancer (11)(12)(13)(14). However, the role of HER4 in CRC remains to be fully elucidated.…”

Convergent and Divergent Cellular Responses by ErbB4 Isoforms in Mammary Epithelial Cells

“…Divergence of signaling processes incited by the four ERBB4 isoforms may explain the discordance in the ERBB4 cancer literature: most studies fail to consider these isoforms separately, and the isoform(s) expressed and subcellular localization of ERBB4 have an impact on prognosis (11, 12). …”