Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients

Abstract

Neuregulin 1 (NRG1), a ligand for human epidermal growth factor (HER) 3 and HER4, can activates cell signaling pathways to promote carcinogenesis and metastasis. To investigate the clinicopathologic significance of NRG1 and its receptors, immunohistochemistry was performed for NRG1, HER3, and HER4 in 502 consecutive gastric cancers (GCs). Furthermore, HER2, microsatellite instability (MSI), and Epstein-Barr virus (EBV) status were investigated. NRG1 gene copy number (GCN) was determined by dual-color fluorescence in situ hybridization (FISH) in 388 available GCs. NRG1 overexpression was observed in 141 (28.1%) GCs and significantly associated with aggressive features, including infiltrative tumor growth, lymphovascular, and neural invasion, high pathologic stage, and poor prognosis (all P < 0.05), but not associated with EBV, MSI, or HER2 status. HER3 cytoplasmic and membranous expression were observed in 157 (31.3%) and 13 (2.6%), respectively. HER4 cytoplasmic expression was observed in 277 (55.2%), including 115 (22.9%) cases with nuclear expression. In contrast to NRG1, cytoplasmic expression of HER3 and HER4 proteins were not associated with survival, but GC patients with HER3 membranous expression showed significantly worse survival. In addition, HER4 nuclear expression was inveresely correlated with patients outcome in GC. NRG1 overexpression was also closely correlated with HER3 (P = 0.034) and HER4 (P < 0.001) cytoplasmic expression. NRG1 GCN gain (GCN ≥ 2.5) was detected in 14.7% patients, including two cases of amplification, and was moderately correlated with NRG1 overexpression (κ, 0.459; P < 0.001). Multivariate analysis identified NRG1 overexpression as an independent prognostic factor for survival (P = 0.040), unlike HER3 and HER4 expression. In 14 HER2positive GC with trastzumab combined chemotherapy, coexpression of NRG1 and HER3 was detected in 2 (14.3%) cases, and these GC patients group with coexpression of NRG1 and HER3 also showed a shorter PFS (P = 0.005).Although our results indicate a lack of prognostic significance of HER3 and HER4 overexpression in GC, overexpression of their ligand, NRG1, was associated with aggressive clinical features and represented an independent unfavorable prognostic factor. Therefore, NRG1 is a potential prognostic and therapeutic biomarker in GC patients.--

Ligand-Independent Epidermal Growth Factor Receptor Overexpression Correlates with Poor Prognosis in Colorectal Cancer

“…HER4 activation generates two structurally and functionally different isoforms by alternative splicing: CYT1 and CYT2. While the CYT2 isoform can enter the nucleus easily and regulates transcription related to favorable features including cell differentiation, the CYT1 isoform is insufficient to translocate into the nucleus and contains a phosphatidylinositol-3 kinase binding motif to activate its signaling pathway to induce tumor cell proliferation [ 13 , 14 ]. These findings suggested that, as for staining patterns, nuclear accumulation of HER4 might indicate better prognosis, in contrast to cytoplasmic localization that is associated with tumor progression [ 12 ].…”

“…These findings suggested that, as for staining patterns, nuclear accumulation of HER4 might indicate better prognosis, in contrast to cytoplasmic localization that is associated with tumor progression [ 12 ]. We previously reported that HER4 nuclear expression might be regarded as a favorable prognostic marker in gastric cancer [ 13 ]. However, clinicopathologic significance depending on the subcellular localization of the HER4 protein was not fully evaluated in CRC.…”

“…In brief, the slides from the TMA blocks with 4-μm thickness were deparaffinized and rehydrated. Then, these slides were placed for antigen retrieval and incubated with antibodies [ 13 , 16 , 17 ]. EGFR-positive expression was defined as membranous staining in > 0% of the tumor cells, according to the DAKO EGFR pharmDX assay interpretation guideline.…”

“…The microsatellite instability (MSI) status was determined using five markers of NCI recommended microsatellite loci (BAT-25, BAT-26, D5S346, D17S250, and D2S123) [ 13 ]. Briefly, tissue sections obtained from the tumor area and matching normal colonic mucosa were analyzed for MSI status using an automated DNA sequencer (ABI3731 Genetic Analyzer, Applied Biosystems, Foster City, CA).…”

Targeting HER2-positive gastric cancer with a novel 18F-labeled ZHER2:342 probe

“…HER2 overexpression has been found in approximately 20-30% gastric cancer cases. [10][11][12] Currently, drugs, such as trastuzumab and lapatinib, targeting the HER2-positive gastric cancer are being extensively used as part of the treatment for patients with advanced gastric cancer as they seem to be more effective; 13,14 however, only few studies have been reported on gastric cancer-targeted diagnosis, especially with the HER2 protein as the target.…”