What's New in Breast Cancer? Molecular Perspectives of Cancer Development and the Role of the Oncogene c-erbB-2 in Prognosis and Disease

The oncogene c-erbB-2 is frequently amplified in human breast carcinoma. The c-erbB-2 gene is present as a single copy in normal cells, and has been mapped to chromosome 17 in the region 17q 12-21.32. c-erbB-2 encodes a transmembrane glycoprotein known as p 185. The intracellular component of p185 has tyrosine kinase activity; the extracellular domain has a structure resembling a growth factor receptor. c-erbB-2 amplification, p185 overexpression and levels of transcribed c-erbB-2 specific messenger RNA have been studied in a large number of breast carcinomas using a variety of techniques. In general, overexpression of p185 oncoprotein reflects various levels of DNA amplification, though in some cases amplification can be detected in the absence of overexpression of p185 and similarly overexpression of p185 can be present without detectable levels of c-erbB-2 amplification. This finding suggests that multiple mechanisms may be responsible for overexpression. c-erbB-2 amplification and/or overexpression occurs in almost all cases of high grade duct carcinoma in-situ, but has been reported in only 10%–40 % of infiltrating duct carcinoma. c-erbB-2 amplification or overexpression occurs rarely in invasive lobular carcinoma, and has not been detected in ductal or lobular epithelial hyperplasia, or in atypical ductal or atypical lobular hyperplasia. It is generally believed that c-erbB-2 amplification/overexpression is an important independent prognostic indicator in breast carcinoma, identifying a subset of patients with poor prognosis tumours, particularly if axillary node metasases are present. However, many unanswered questions remain regarding c-erbB-2 and its role in breast cancer development and progression. The causes of c-erbB-2 amplification are unknown. There is no evidence of mutations in the human gene which might cause amplification or overexpression. The significance of the differences in levels of c-erbB-2 amplification/ over-expression in in-situ duct carcinoma and associated invasive duct carcinoma has not been established. Amplification or overexpression have not been reported in atypical duct hyperplasia, a proposed precursor of duct carcinoma in-situ, yet overexpression occurs almost always in high grade duct carcinoma in-situ. c-erbB-2 may play a critical role in the development of a clonal in-situ, proliferation of high histological grade, yet does not obviously influence the acquisition of an invasive phenotype. We would postulate that this instability in amplification/overexpression is of biological significance, and if better understood may aid in the study of progression of human breast carcinoma