ErbB2 overexpression in human breast carcinoma is correlated with p21Cip1 up-regulation and tyrosine-15 hyperphosphorylation of p34Cdc2: poor responsiveness to chemotherapy with cyclophoshamide methotrexate, and 5-fluorouracil is associated with Erb2 overexpression and with p21Cip1 overexpression.

Abstract

Clinical investigations have shown that in patients with breast carcinoma, tumors that overexpress the erb-B2 gene are less responsive to certain chemotherapy regimens compared with tumors that express low levels of ErbB2, suggesting that ErbB2 overexpression may be used as a marker for poor response to chemotherapy in patients with breast carcinoma. The combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) is one of the most widely used chemotherapy regimens in patients with breast carcinoma. Patients who have ErbB2-overexpressing breast carcinomas have poorer responses to CMF compared with patients who have breast carcinomas with low ErbB2 expression. ErbB2-overexpressing breast tumor cells are resistant to taxol-induced apoptotic cell death. The underlying molecular mechanism is that ErbB2 inhibits p34(Cdc2) activation, which is required for taxol-induced apoptosis, by up-regulating p21(Cip1) and by hyperphosphorylating p34(Cdc2) on tyrosine-15. However, the relation between ErbB2, p21(Cip1), and p34(Cdc2) in patients with breast carcinoma remains elusive. The contribution of these molecular alterations to ErbB2-mediated CMF resistance has not been examined.