Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma.

The epidermal growth factor receptor (EGFR) family plays an important role in breast carcinogenesis. Much interest has been focused recently on its members because of their potential role as prognostic indicators in breast cancer and their involvement in cancer therapy. We have evaluated more than 1500 cases of invasive breast carcinoma immunohistochemically using tissue microarray technology to examine the expression of EGFR family receptor proteins. We have found that 20.1 and 31.8% of cases were positive for EGFR and c-erbB-2, respectively, and 45 and 45.1% of tumours overexpressed for c-erbB-3 and c-erbB-4, respectively. The expression of either EGFR or c-erbB-2 was associated with other bad prognostic features and with poor outcome. Neither c-erbB-3 nor c-erbB-4 had any association with survival. c-erbB-2 had an independent prognostic effect on overall and disease-free survival (DFS) in all cases, as well as in the subset of breast carcinoma patients with nodal metastases. Several hetero- and homodimeric combinations have been reported between the EGFR members. Those dimers can evoke diverse signal transduction pathways with variable cellular responses. We stratified cases according to their co-expression of receptors into distinct groups with different receptor-positive combinations. Patients whose tumours co-expressed c-erbB-2 and c-erbB-3, as well as those whose tumours co-expressed EGFR, c-erbB-2 and c-erbB-4 showed an unfavourable outcome compared with other groups, while combined c-erbB-3 and c-erbB-4 expression was associated with a better outcome. In cases showing expression of one family member only (homodimers), we found a significant association between c-erbB-4 homodimer-expressing tumours and better DFS. In contrast, patients with c-erbB-2 homodimer-expressing tumours had a significant poorer DFS compared with other cases. These data imply that the combined profile expression patterns of the four receptor family members together provide more accurate information on the tumour behaviour than studying the expression of each receptor individually.

Expression of the transcription factor CTCF in invasive breast cancer: a candidate gene located at 16q22.1.

CTCF is a ubiquitous 11-zinc-finger protein that plays a role in gene silencing or activation, chromatin insulation and genomic imprinting. The CTCF gene has been mapped to the chromosome band 16q22.1 that shows frequent loss of heterozygosity in breast cancer. The E-cadherin gene is the known tumour suppressor gene (TSG) at this region in lobular carcinomas; however, the target gene in the more frequent ductal tumours is still unknown. Since CTCF targets include TSGs and oncogenes and it has the ability to inhibit cell growth and proliferation, it has been suggested that it may be the target gene at the 16q22.1 in ductal carcinomas. In the present study, tissue microarray technology was used to study the expression pattern of CTCF immunohistochemically in 344 cases of invasive breast carcinoma and its expression was correlated with clinicopathological variables and patient outcome. Results showed that breast tissues express CTCF in the parenchymal cells of the normal ducts and lobules but with a variable percentage of positive cells. Staining of CTCF was detected in the nuclei and cytoplasm of the malignant cells, but no significant loss or decrease of expression was noticed in association with any specific tumour type. There was a significant correlation between expression of CTCF and histological grades; lower expression was associated with grade 3 tumours. Cytoplasmic expression was associated with increased tumour size and with the presence of vascular invasion. However, no association was found between CTCF expression and tumour type, lymph node stage, oestrogen receptor expression or patient outcome. In conclusion, the current results show that CTCF, although it may play a role in breast carcinogenesis, is unlikely to be the TSG targeted by the 16q22.1 loss in breast cancer and thus another gene or genes at this region remain to be identified.