Clinical and experimental evidence supports a role for overexpression of the HER2 protooncogene in the progression of human breast, ovarian, and non-small cell lung carcinoma.
High levels of expression of the c-erbB-2/neu gene have been reported in non-small-cell lung cancer (NSCLC) cell lines and primary tumors from the United States.
The purpose of this study was to investigate the relationships between chemoresistance and the presence of ras gene point mutations and overexpression of the HER-2/neu gene in NSCLC cell lines, which indicates gene activation.
However, information concerning three oncogenes may soon prove to be helpful in the clinical arena: the myc genes in SCLC, and the ras genes and c-erbB-2 in NSCLC.
Using a panel of 20 non-small cell lung cancer (NSCLC) cell lines established from previously untreated patients, we investigated the relationships between intrinsic chemoresistance (to four agents used commonly in the therapy of NSCLC) and HER-2/neu gene expression (which encodes glycoprotein p185neu), p53 gene mutations, and cell proliferation characteristics.
We concluded that sialomucin expression is also a poor indicator of prognosis, which is associated with erbB-2 oncoprotein overexpression, early postoperative recurrence, and cancer death in NSCLC.
Thus, a prospective analysis of the co-expression of Bcl-2 + HER2 in NSCLC patients may identify patients with a poor prognosis who may benefit from more aggressive therapy.
From the results obtained in this study the following conclusions can be drawn: (a) c-erbB-2 hyperexpressing NSCLC are associated with abnormalities in other biological markers and with a greater rate of relapses; (b) SSCP seemed to be more specific that IHC to detect p53 molecular abnormalities; and (c) the D.I. is the parameter more tightly related with relapse.
Using a FDA-approved standardized diagnostic kit, HercepTest, for detection of HER-2/neu in clinical specimens, we examined the expression of HER-2/neu in NSCLCs in archival paraffin-embedded specimens (N = 81).
NSCLC cell lines (H460, H358, H322, or H661) were assayed for expression of erbB1 and erbB2, the cell adhesion molecule E-cadherin, secretion of the matrix metalloproteinase 9 (MMP-9), and vascular endothelial cell growth factor (VEGF), as well as their ability to invade Matrigel after 48-hour exposure to 17AAGA.
This study demonstrates that testing 3 molecular markers (c-Ki-ras, p53 and c-erbB-2) improves estimation of prognosis compared to single marker testing and appears to define low (82.6%+/-7.9% 5-year survival) and high risk (40.2%+/-5.5% 5-year survival) groups for treatment failure in potentially curative (RO) resected NSCLC.
The finding that high levels of EGFR showed very little influence on the relationship between p185neu and cisplatin resistance suggests that EGFR may be a less crucial factor in modulating the chemoresistance of NSCLC cells when compared with HER-2/neu.
Testing of molecular marker coexpression (EGFR and HER2-neu) improves the estimation of prognosis and appears to define low- and high-risk groups for treatment failure in curatively resected NSCLC.
We conclude that c-erbB2 is a marker of tumour progression in NSCLC which can be observed on protein level and reflects chromosomal alterations at 17q21.
By FACS, we found Her-2/neu overexpression (mean fluorescence intensity >8) in 2 of the 22 non-small cell lung cancer (NSCLC) cell lines (9%), none of 11 small cell lung cancer (SCLC) cell lines, and 4 of 5 breast cancer cell lines.
Future studies in NSCLC need to include immunohistochemistry and fluorescence in situ hybridization analysis to determine the method of choice for evaluating clinically relevant HER2/neu-positive tumors.