WHATS 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 carcinom a(66). 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(121). c-erbB-2 encodes a transmembrane glycoerotein known as p185. The intra cellular component of p185 has tyrosine kinase activity; the extracell ular domain has a structure resembling a growth factor receptor. c-erb B-2 amplification, p185 overexpression and levels of transcribed c-erb B-2 specific messenger RNA have been studied in a large number of brea st carcinomas using a variety of techniques. In general, overexpressio n of p185 oncoprotein reflects various levels of DNA amplification, th ough in some cases amplification can be detected in the absence of ove rexpression of p185 and similarly overexpression of p185 can be presen t without detectable levels of c-erbB-2 amplification. This finding su ggests that multiple mechanisms may be responsible for overexpression( 78). 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 n ot been detected in ductal or lobular epithelial hyperplasia, or in at ypical ductal or atypical lobular hyperplasia. It is generally believe d that c-erbB-2 amplification/overexpression is an important independe nt prognostic indicator in breast carcinoma, identifying a subset of p atients with poor prognosis tumours, particularly if axillary node met asases are present. However, many unanswered questions remain regardin g 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 ove rexpression. The significance of the differences in levels of c-erbB-2 amplification/overexpression in in-situ duct carcinoma and associated invasive duct carcinoma has not been established. Amplification or ov erexpression have not been reported in atypical duct hyperplasia, a pr oposed 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 acqui sition of an invasive phenotype. We would postulate that this instabil ity in amplification/overexpression is of biological significance, and if better understood may aid in the study of progression of human bre ast carcinoma.