The subcellular localization of the neu protein in human normal and neoplastic cells

SummaryIn a retrospective study the expression of the c-erbB-2 oncogene was determined immunohistochemically in 276 breast cancer samples from 253 patients with the antibody 21N. The follow-up period was between 7 and 12 years. This study showed a trend for an inverse relationship between c-erbB-2 positive tumours and estrogen receptors (ER). A correlation was assessed between c-erbB-2 positive tumours and histological grade, liver metastases as first site of metastases, disease free survival time (DFS) in the second and third year after diagnosis and overall survival time (OST) in the third and fourth year after diagnosis. A trend was seen between c-erbB-2 positive tumours and tumour size. No correlation was found between c-erbB-2 positive tumours and age at diagnosis. The method of operation and lymph node involvement. From this study we conclude that there is a significant difference in prognosis the first years after diagnosis, but this difference seems to vanish in a longer follow-up period of 12 years. This provides us with an explanation for the discrepancies in literature concerning c-erbB-2 expression and prognosis in breast cancer. Some investigators did not show differences in prognosis between positive and negative cases after a long follow-up period whereas investigations with a short term follow-up period up to 2-3 years have indeed established a more aggressive behaviour of c-erbB-2 overexpressionary tumours.

Section: Discussionsupporting

confidence: 89%

“…Membrane staining with antibodies against the cerbB-2 protein is known to be related to DNA amplification (Venter et al, 1987;Gusterson et al, 1988;Walker et al, 1989) and is considered to be the only expression of the c-erbB-2 oncogene, as cytoplasmic staining was shown not to be related to c-erbB-2 expression (De Potter et al, 1989b).…”

Section: Discussionmentioning

confidence: 99%

c-erbB-2 positive breast tumours behave more aggressively in the first years after diagnosis

Schroeter

Potter²,

Rathsmann³

et al. 1992

“…The cytoplasmic staining of p185 c-erbB-2 has already been reported in prostate cancers (Rosset et al, 1993). De Potter et al (1989) have described the presence of a protein on the mitochondrial membrane, appearing as granular staining in the cytoplasm. The significance of the cytoplasmic staining in breast cancer cells is controversial, since some authors did not observe a correlation between the cytoplasmic protein and the mRNA levels (DiGiovanna, 1999;Ross and Fletcher, 1999 have analysed, there was a good correlation between these parameters.…”

Section: Discussionmentioning

confidence: 99%

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Vernimmen¹,

Guéders²,

Pisvin

et al. 2003

The ERBB2 gene is overexpressed in 30% of breast cancers and this has been correlated with poor prognosis. ERBB2 is upregulated in other cancers such as prostate, pancreas, colon and ovary. In breast cancer cells, the mechanisms leading to ERBB2 gene overexpression are increased transcription and gene amplification. In these cancers, AP-2 transcription factors are involved in ERBB2 overexpression, and AP-2 levels are correlated with p185 c-erbB-2 levels. In this work, we wanted to know if the same molecular mechanisms are responsible for the ERBB2 upregulation in non-breast cancers. We compared ERBB2 gene copy number, p185 c-erbB-2 and mRNA levels with AP-2 levels in several ovary, prostate, colon and pancreas cancer cells. A moderate expression of erbB-2 mRNA and protein were observed in some cells without gene amplification. In contrast to breast cancer cells, AP-2 factors were absent or low in some non-breast cells which did express ERBB2. It is thus likely that AP-2 is not a major player in the increased levels of erbB-2 transcripts in non-breast cancer cells. The transcriptional activity of the ERBB2 promoter in colon and ovary cancer cells was estimated using reporter vectors. The results showed that the promoter regions involved in ERBB2 gene overexpression in breast cancer cells are different from those that lead to the gene upregulation in colon and ovary cancers. In conclusion, our results indicate that different transcriptional and post-transcriptional mechanisms are responsible for the increased levels of erbB-2 transcript and protein in breast and non-breast cancer cells.

“…De Potter et al (1989) have suggested that these may represent the c-erbB-2 cell membrane protein and a 155 kD protein associated with the mitochondrial membrane. The smaller of these may represent a partially glycosylated form of the protein since inhibition of N-linked glycosylation by tunicamycin has been shown to produce an immunoprecipitable protein of 155-160kD in human cells which express c-erbB-2 .…”

Section: Discussionmentioning

confidence: 99%

Amplification and over-expression of c-erbB-2 in transitional cell carcinoma of the urinary bladder

Coombs

Pigott²,

Sweeney³

et al. 1991

163

Summary The structure and expression of the proto-oncogene c-erbB-2 was studied in 86 patients with transitional cell carcinoma. Initial tissue samples comprised 37 grade 1, 32 grade 2 and 13 grade 3 tumours and four cases of carcinoma in situ. At the time of this first tumour sample, amplification of the c-erbB-2 gene was demonstrated by Southern blotting in 1/37 grade 1, 5/32 grade 2 and 6/13 grade 3 tumours (0.005< P<0.01). Tumour 're-occurrences' were obtained from 23 of these patients on one or more occasions. Amplification was detected in re-occurrences from seven of these 23, none of whom showed amplification in the first tumour sample. DNA was also extracted from exfoliated cells in urine collected from five cases of carcinoma in situ and c-erbB-2 amplification was demonstrated in one of these. No gene amplification was identified in patients' lymphocytes, ten biopsies of normal urothelium and 22 various intravesical pathologies. Increased expression of c-erbB-2 mRNA correlated with amplification of the gene. In addition, raised levels of mRNA were seen in the absence of gene amplification in six tumours. Immunoblotting using the polyclonal antibody 21N, raised against the c-terminus of the c-erbB-2 protein demonstrated increased amounts of a 185 kD immunoreactive protein in tumours with increased c-erbB-2 gene copy number compared with control tissues. In some tumours with high c-erbB-2 gene copy number, a 155 kD immunoreactive protein not detected in controls was expressed at higher level than the 185 kD protein. Immunocytochemistry using a monoclonal antibody AB-3, raised against the c-terminus of the c-erbB-2 protein, showed a positive reaction in the cytoplasm and cell membrane of tumours with gene amplification and in 40% of tumours with no amplification. An association was found between c-erbB-2 amplification and over-expression and the development of tumour re-occurrences. We suggest that c-erbB-2 amplification and over-expression may provide a useful molecular marker in transitional cell carcinoma of the bladder and merits further investigation as a potential prognostic indicator.Transitional cell carcinoma of the bladder is the fourth most common cancer in males in the United Kingdom (HMSO,