Breast Cancer Research and Treatment 28: 261-266, 1993. © 1993 Kluwer Academic Publishers. Printed in the Netherlands. Report Concurrent abnormal expression of ERBB-2, EGFR, and p53 genes and clinical disease progression of breast carcinoma Daniel W. Visscher, 1Rudolph Castellani, ~Susan Mary Wykes, l Fazlul H. Sarkar 1and Mohamed E. Hussain 2 1Frorn the Departments" of ~Pathology and 2 Biostatistics, Wayne State University School of Medicine and Harper Hospital, Detroit, Michigan, USA Key words: breast carcinoma, EGF receptor, immunoperoxidase, oncogenes, tumor suppressor genes Abstract Metastatic phenotype in human solid tumors is believed to follow stochastic acquisition of structural genetic aberrations-so-called multistep tumor progression. We tested this hypothesis in breast carcinoma by immu- nostaining 89 stage-heterogeneous cases for the products of three genes (p53, ERBB-2, and EGFR) which are frequently altered in this tumor system. Variable relationships were observed between advanced disease stage and imnmnostaining for individual gene products (ERBB-2 - p -- 0.05, EGFR - p = 0.02, p53 - p = 0.12, Chi Square test). Regional or distant metastases at presentation correlated with multiple oncogene/tumor sup- pressor gene expression abnormalities: node negative - 59% none positive, 29% one positive, 12% two or more positive, vs. node positive - 37% none positive, 23% one positive, 39% two or more positive (p = 0.01). Only 2/12 (17 %) of tumors with distant metastases at presentation were negative for abnormal expression of any of these gene products, and 7/12 (58%) were positve for two or three. Among axillary node negative patients who developed recurrences, 67 % exhibited staining for at least one gene product, compared to only 27% of those without recurrences (p = 0.02). All 5 cases with abnormal staining for each gene product had regional or distant metastases at presentation and recurred. In multivariate analysis, individual expression of p53 outweighed expression of ERBB-2 and EGFR in correlation with outcome. These data suggest clinical neoplastic progression of breast carcinomas correlates with cumulative genetic events detectable by protein expression. Short term recurrence, however, may correlate more closely with abnormal expression of p53 than with EGFR or ERBB-2. Introduction Current theory of neoplastic development and pro- gression holds that genetic instability causes step- wise evolution of phenotypic traits required for in- vasion and metastasis [1, 2]. Accordingly, human solid tumors display a wide spectrum of structural genetic pathology which is presumed to reflect this process, including gross DNA content shifts (DNA aneuploidy), karyotype anomalies (such as translo- cations), and numerous molecular level changes (including point mutations, allelic losses, and gene amplifications). The sheer variety of genetic alter- ations observed within and between individual neo- plasms indicates tumor progression is both complex and heterogeneous. This limits the biological signif- icance of any particular genetic anomaly and im- plies clinical tumor progression is caused by dereg- ulated cell growth and differentiation produced by the cumulative effect of multiple genetic events. Address for offprints: D.W. Visscher, Department of Pathology, Harper Hospital, 3990 John R, Detroit, MI 48201, USA