BACKGROUNDAberrant activation of the β‐catenin signaling pathway has been implicated in several malignancies, including breast carcinoma. Recently, it was shown that p53 down‐regulated β‐catenin in a complex fashion. The authors examined the expression of β‐catenin, key members of its signaling pathway, and p53 in a large cohort of breast tumors.METHODSThe authors conducted an immunohistochemical analysis of the expression of β‐catenin, upstream modulators (HER‐2/neu, Met, and epidermal growth factor receptor [EGFR]), downstream target genes (cyclin D1 and matrix metalloproteinase‐7 [MMP7]), and p53 on a tissue microarray of 346 lymph node‐negative breast carcinomas. The results were correlated with one another and with standard clinicopathologic parameters.RESULTSβ‐Catenin expression was observed in the membrane and/or cytoplasm without any significant nuclear expression. HER‐2/neu and EGFR were observed on the membrane in 21% and 6% of tumors, respectively, and Met stained in a membrane/cytoplasm distribution in 28% of cases. Cyclin D1 was expressed in the nucleus and MMP7 was expressed in the cytoplasm in 26% and 75% of tumors, respectively. Nuclear expression of p53 was noted in 31% of tumors. When each marker was analyzed separately, only p53 and Met demonstrated a significant correlation with survival. However, patients who had tumors that coexpressed high levels of β‐catenin and p53 had markedly worse overall survival (P = 0.0026). In multivariate analysis, only tumor size, Met, and the coexpression of β‐catenin and p53 retained statistical significance.CONCLUSIONSThe current findings support a potential synergistic effect of abnormal β‐catenin regulation and p53 status in the pathogenesis and natural history of lymph node‐negative breast carcinoma. Furthermore, the results show that a combined analysis of multiple markers, notably β‐catenin and p53, may enhance the prognostic capabilities compared with individual markers. Cancer 2004. © 2004 American Cancer Society.