Concurrent overexpression of p53 and c-erbB-2 correlates with accelerated cycling and concomitant poor prognosis in node-negative breast cancer

Simultaneous overexpression of c-erbB-2 and p53 has been reported to be pro gnostically unfavorable in breast cancer. Herein, we show that concurrent o verexpression of these 2 proteins is associated with a marked reduction in the relative fraction of cells in G(1) phase of the cell cycle, indicating an accelerated cell cycle progression. Using an immunohistochemical approac h, we examined 261 cases of node-negative infiltrating ductal carcinomas of the breast with respect to c-erbB-2 and p53 expression and to the prolifer ative activity measured by the Ki-67 index. By means of a novel monoclonal antibody, Ki-S2, which exclusively recognizes proliferating cells in the S, G(2), and M phases of the reproductive cycle, we were further able to calc ulate the relative fraction of the cells having passed the restriction poin t at the G(1)/S boundary, thus defining a cycling ratio (CR). The results w ere correlated with clinical outcome; median follow-up time was 96 months. Tumors that simultaneously overexpressed c-erbB-2 and p53 had a high median CR and followed an unfavorable course. However, increased CRs were also ob served independently of c-erbB-2 and p53 overexpression, suggesting that ot her molecular mechanisms may contribute to acceleration of cell cycle progr ession. In a multivariate analysis that included patient age, tumor size, h ormone receptor status, c-erbB-2 and p53 expression, and the Ki-67 index, C R emerged as the most significant independent predictor of overall and dise ase-free survival (P < .0001). It is concluded that the CR is a gauge of ce ll cycle deregulation and therefore may be a powerful indicator of the biol ogic behavior of cancers. HUM PATHOL 32:311-319. Copyright (C) 2001 by W.B. Saunders Company.