MOLECULAR-BIOLOGY OF BREAST-CANCER

Background: A gene responsible for an inherited predisposition to breast and ovarian cancer has been localized to the long arm of chromosome 17 and termed BRCA1. As well as being closely linked to breast/ovarian cancer cases, this gene may be involved in up to 45% of site-specific breast cancers. The identification and cloning of the BRCA1 gene is imminent, and will facilitate the screening and counselling of families at risk of breast cancer, and in the longer term may open up new therapeutic possibilities. The tumour suppressor gene TP53 is mutated in 25%-40% of cases of sporadic breast cancer, and is associated with an aggressive tumour phenotype and poor prognosis in both node-positive and node-negative cases. The pattern of mutations in this tumour suppressor gene shows a higher than expected frequency of G to T transversions, mostly restricted to the highly conserved domain in exons 5 to 8. In many, but not all cases, point mutation of one allele is accompanied by deletion of the remaining normal allele at chromosome 17p13. Abnormalities of TP53 appear to be relatively early events in tumorigenesis, being present in ductal carcinoma in situ lesions. The retinoblastoma gene RB1 shows a variety of abnormalities in about 20% of breast cancers, and there may be an association with TP53 mutations. Other abnormalities which occur with a particularly high incidence in breast cancer include allele loss at chromosome 1p/1q, 3p, 6q, 11p, 16q and 18q. The ERBB2 oncogene encodes a transmembrane receptor tyrosine kinase whose ligand has recently been claimed to be the heregulin family in man. Overexpression of ERBB2 is a marker of poor prognosis in both node-positive and nodenegative disease, and also a marker of poor response to endocrine therapy and conventional cytotoxic therapy. A number of specific therapies are being developed against this oncoprotein including inhibitory monoclonal antibodies, tyrosine kinase inhibitors, dimerization inhibitors and antisense technology. New development: The identification of a novel transcription factor (OB2-1), which appears to be an important contributor to ERBB2 overexpression in breast cancer, has been an exciting development, which may also present therapeutic possibilities.