proximately 10 to 30 percent of breast carcinomas and also in adenocarcinomas of salivary gland, stomach, and ovary. erbB-2 is structurally related to the EGF receptor; hence, its gene product is thought to be a growth factor, but its ligand is unknown. Some investigators have shown that erbB-2 amplification and protein overexpression correlate with poor prognosis; others have found no such correlation. The evidence for association of erbB overexpression with poor prognosis is stronger in patients with lymph node metastases than in node-negative patients.

Much less is known about the role in breast cancers of erbB-3, a third member of the erb family. It was identified because it is homologous to the EGF receptor gene and to erbB-2. Sequence analysis of the cDNA predicts that it encodes a 148-kD transmembrane polypeptide. Like the other members of this family, overexpression of erbB-3 occurs in a percentage of breast cancers.

Amplification of int-2 and myc

There are four known int genes, which are defined as the sites of common integration of the mouse mammary tumor virus genome. Their sequences fall into two groups: int-1 and int-2. Although the two groups have no sequence similarity, both are implicated in mouse mammary tumorigenesis and are essential in early embryogenesis.

int-1 related genes are not amplified, translocated, or even expressed in human breast cancer. In contrast, the int-2 gene is amplified in 15 percent of breast cancers. It is unlikely, however, that the int-2 gene itself is important in breast cancer. Whenever gene amplification occurs, the gene that confers a selective advantage is coamplified, together with 100 to 1,000 kilobases of surrounding DNA. The int-2 gene is usually coamplified with certain other genes that have been implicated in human cancer, including hst, bcl-1, and sea. In a minority of breast cancers, bcl-1 is the only gene of the cluster that is amplified; in some cases, none of the three genes is expressed. There is hence some question of which gene is the driving force in the amplicon, and it has been hypothesized that an as yet unknown gene in the region, when amplified, confers a selective growth advantage on breast cancers.

Much less work has been done on the role of c-myc in breast cancer. C-myc is a nuclear protein that may be involved in transcriptional regulation of other genes important for cellular growth control. Amplification of the c-myc gene has been observed in approximately 5 to 30 percent of breast cancers.



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