The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients

Abstract

Increased expression of the epidermal growth factor (EGF) receptors, HER1 and HER2 are related to poor prognosis in most cancers studied. Recently, a high expression of the two remaining receptors of the EGF system, HER3 and HER4 has been related to a favourable prognosis. However, prognostic significance of HER1 and HER2 receptors in bladder cancer is controversial and the effect of the expression of different combinations of these receptors on patient survival is not well understood. Therefore, we examined the mRNA expression of all four EGF receptors with real-time polymerase chain reaction in biopsies from 88 patients with bladder cancer, where the survival was followed for a median of 38.5 months (range 1 -117 months). Expression of HER1 and HER2 alone showed no correlation with survival. However, a high expression of HER1 together with high expression of HER3 and HER4 correlated to a better prognosis compared to the high expression of HER1 together with low expression of HER3 and HER4 (P ¼ 0.0006). Also, a significantly longer survival was observed in patients expressing high HER2 when coexpressed with high HER3 and HER4, as compared to the survival in patients with tumours expressing high HER2 but low HER3 and HER4 (P ¼ 0.0005). Our results suggest that the final outcome of patients with high HER1-and HER2-expressing tumours depends on the expression of HER3 and HER4.

Distinctive Expression Pattern of ErbB Family Receptors Signifies an Aggressive Variant of Bladder Cancer

“…6 Similarly, reports regarding the association between the levels of ErbB-3 and prognosis are also conflicting. 6,15,19,20 Differences in both the incidence and the prognostic significance of ErbB-2 and ErbB-3 expression are very likely attributable to the use of different methodologies, including assessment of receptor status (i.e., detection of amplification vs. detection of over-expression), method employed (i.e., polymerase chain reaction, fluorescent in situ hybridization, immunohistochemistry), and definition of receptor positivity.…”

The ERBB3 receptor in cancer and cancer gene therapy

“…280 This was confirmed in a further study, where high expression of EGFR or ERBB2 predicted poor survival only when ERBB3 and ERBB4 had low expression. 281 RT4 bladder carcinoma cells were treated with mitogenic HB-EGF, resulting in increased mRNA expression of ERBB3, ERBB4, NRG1α and NRG1β, whereas expressions of NRG2α, NRG2β and NRG4 were decreased. 282 These findings point to positive and negative regulatory interactions involving all four ERBB family members and several NRGs in cancers of this cell type.…”

Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant

“…All PCR reactions were performed using a Lightcycler instrument and the Sybr Green I real time PCR kit both from Roche and quantifications are presented as the ratio between the amount of target gene and the amount of β-actin mRNA in each sample, as previously described [22]. For primer sequences and PCR profiles please see [23] (ErbB1-4), [22] (hrg1-4) or [24] (EGF, TGFα, HB-EGF, betacellulin, amphiregulin and epiregulin).…”