Oncogenes in breast cancer

Abnormalities in a number of oncogenes have been associated with breast cancer including HER2, SRC, MYC and RAS.

HER2 (also known as NEU or ERBB2) is involved in the regulation of normal breast development and over-expression has been associated with breast cancer and subsequently with ovarian cancer (Slamon et al., 1989). HER2 amplification has been seen in 20%-30% of breast cancers. The clinical utility of HER2 has received considerable attention over the last 15 years. Initial studies showed that amplification independently predicted a more aggressive disease and reduced overall survival and disease-free interval in node-positive patients (Slamon et al., 1987, 1989). Subsequently many studies have been carried out to try to confirm these findings. Multivariate analysis of over 15 000 patients from 47 studies has shown that, in the majority of studies and the majority of patients, HER2 amplification was associated with a worse prognosis in node-positive patients (Ross and Fletcher, 1998). Studies on HER2 status in node-negative individuals, however, remain conflicting (Ross and Fletcher, 1998). The American Society of Clinical Oncology has recommended that HER2 status of all primary breast cancers should be determined at diagnosis or recurrence (Bast et al., 2001). HER2 testing has therefore become part of the routine work-up of breast cancer patients at many centres. A humanised monoclonal antibody (Her-ceptin, trastuzumab) to the HER2 protein has been developed which abolishes HER2 function and inhibits tumour growth, and determination of HER2 status is required for patients who are to undergo treatment with Herceptin. Studies have shown, perhaps not surprisingly, that the higher the level of HER2 amplification or over-expression, the greater the response rate to the antibody.

SRC kinase activity in breast cancer has been found at 4-20 times the level of that seen in normal tissues. One reason for this increase appears to be related to increased phosphatase activity which dephosphorylates the SRC Tyr530 regulatory site resulting in SRC activation (Egan et al., 1999). SRC primarily appears to be involved in the progression and metastasis of cancers and it has been suggested as a possible target for anti-cancer therapies. However, so far there are no diagnostic or prognostic implications for SRC activation.

Amplification of MYC is well recognised in breast cancers, although the frequency with which this occurs varies from one study to the next varying from 1% to 94%. A meta-analysis of 29 separate studies examined showed the average frequency of amplification to be 15.5% (Deming et al., 2000). This analysis showed that amplification had significant but weak associations with tumour grade, lymph node metastasis, post-menopausal status and negative progesterone receptor status, although the only feature reaching statistical significance was the last. Amplification was significantly associated with the risk of relapse and death. However, reports on the prognostic value of amplification and prognosis of MYC amplification are conflicting. The major reasons for the wide differences in findings are due to the variation in the sensitivities of the technology used, the small size of studies and to variation in the tumour grades studied. A review of MYC amplification in breast cancer highlights these problems (Liao and Dickson, 2000).

Point mutations in the RAS family are not commonly associated with breast cancer. However, over-expression of the RAS p21 protein has been found in up to 83% of cases. Several immunohistochemical studies have shown a correlation between over-expression of RAS and a better prognosis but only in the group of node-negative patients (Gohring et al., 1999; Schondorf et al., 2002). However, as with MYC gene abnormalities, reports on the role of RAS abnormalities are conflicting and some studies have associated over-expression of RAS with progression and poor prognosis. Again the reasons for these differences are almost certainly due to variations in methodology, studies involving small patient numbers and variations in the patient groups investigated.

Polymorphisms of the HRAS microsatellite located downstream of the HRAS gene have been investigated in breast cancer. Meta-analyses have shown that women with a single copy of one of the rare alleles of this polymorphism have a 1.7-fold increased risk of breast cancer compared with the general population, whilst those who are homozygous for the rare allele are at a 4.6-fold increased risk (Krontiris et al., 1993).

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