β‐Catenin and p53 analyses of a breast carcinoma tissue microarray

Abstract

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.

P53 levels determine outcome during β-catenin tumor initiation and metastasis in the mammary gland and male germ cells

“…Given the role of P53 in apoptosis, observing high levels of P53 in a pathology sample is indicative of mutation in the P53 apoptotic pathway. Therefore, the findings of Chung et al (2004) are consistent with our results that the combination of aberrant b-catenin and dysfunctional P53 leads to a more aggressive and metastatic tumor. These results have important implications related to the usefulness of multiple prognostic markers when analyzing tumors in the clinic.…”

“…Chung et al (2004) observed that the presence of high levels of b-catenin protein in combination with high levels of P53 in the primary tumors of lymph node negative breast cancer patients correlated with a worse survival than patients displaying high levels of either protein alone. Given the role of P53 in apoptosis, observing high levels of P53 in a pathology sample is indicative of mutation in the P53 apoptotic pathway.…”

“…b-catenin is stabilized in 50% of human breast carcinomas and the elevated levels of b-catenin correlate with increased cyclin D1 expression and poor prognosis (Lin et al, 2000;Ryo et al, 2001). Furthermore, in lymph node negative breast tumors, the presence of high levels of b-catenin protein in combination with high levels of P53 protein correlated with poor survival of patients (Chung et al, 2004), indicating that b-catenin and P53 may have a combinatorial effect on tumor progression. In addition to the human data, studies using mouse models have demonstrated a role for b-catenin in initiating mammary tumors (Imbert et al, 2001;Michaelson and Leder, 2001).…”

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

“…Immunohistochemical staining carried out by several groups has demonstrated elevated levels of nuclear and/or cytoplasmic b-catenin in breast tumours with significant frequency (Lin et al, 2000;Ryo et al, 2001;Chung et al, 2004). Lin et al (2000) also showed that nuclear and/or cytoplasmic staining of b-catenin correlated with elevated cyclin D1, which is one of the known targets of b-catenin/TCF transcription.…”

“…This signalling pathway is strongly implicated in tumorigenesis; indeed, the first mammalian Wnt isoform was identified based on its ability to promote mouse mammary tumorigenesis (Polakis, 2000). In addition, aberrant nuclear and cytoplasmic localisation of b-catenin is frequently observed in human breast cancer (Lin et al, 2000;Ryo et al, 2001;Chung et al, 2004). In contrast to colorectal cancer (CRC), however, mutation of APC, AXIN or CTNNB1 (b-catenin) is rare in breast cancer, indicating that other mechanisms are responsible for the activation of b-catenin.…”