Study of phospho-β-catenin subcellular distribution in invasive breast carcinomas in relation to their phenotype and the clinical outcome

Abstract

b-Catenin has a crucial role in cell-cell adhesion as well as a signaling role as a member of the Wnt pathway. The aim of this study was to examine the clinicopathological and prognostic value of phosphorylated b-catenin, as well as its relation to the tumors' phenotype, in breast cancer. Immunohistochemistry was applied on 141 paraffin-embedded breast tissue specimens for the detection of phospho-b-catenin, ER, PR, c-erbB-2, p53, Ki-67, bcl-2, uPAR and TIMP-1. For each case, a phospho-b-catenin index was determined by image analysis. Phospho-b-catenin staining was detected in the cytoplasm and the nucleus of the malignant cells. Cytoplasmic phospho-b-catenin was statistically higher in carcinomas of smaller tumor size (P ¼ 0.030), lower stage (P ¼ 0.026), decreased Ki-67 and high c-erbB-2 immunoreactivity (P ¼ 0.052 and P ¼ 0.037, respectively). Nuclear phospho-b-catenin showed a parallel correlation with ER and ERb (P ¼ 0.022 and P ¼ 0.043, respectively), bcl-2 (P ¼ 0.042), uPAR in cancer cells (P ¼ 0.041) and TIMP-1, although the correlation was borderline (P ¼ 0.066). Cytoplasmic phospho-b-catenin was found to be independently correlated with prolonged disease-free and overall survival (P ¼ 0.046 and P ¼ 0.002, respectively), whereas nuclear localization was correlated with a shortened overall survival (P ¼ 0.046). In conclusion, phospho-b-catenin may have a different involvement in invasive breast carcinomas, according to its subcellular distribution. Nuclear localization seems to be related to an aggressive tumor phenotype, negatively affecting patients' overall survival, whereas cytoplasmic localization is associated with a favorable tumor phenotype and a longer disease-free and overall survival.

Dickkopf-1 in human oral cancer

“…Some studies have shown that phosphorylated β-catenin was immunodetected in both the cytoplasm and nuclei of cancer cells (21) and that phosphorylated β-catenin expression was localized almost exclusively in the nuclei in cancers, such as melanoma and colorectal cancer (20,40). Nuclear localization of phosphorylated β-catenin may be related to changes at other stages in the signaling pathway (20)(21)(22)(23)40). A high level of nuclear phosphorylated β-catenin was involved in the increased invasiveness phenotype and in the low survival rates of melanoma and breast cancer (20,21).…”

“…A high level of nuclear phosphorylated β-catenin was involved in the increased invasiveness phenotype and in the low survival rates of melanoma and breast cancer (20,21). Because nuclear phosphorylated β-catenin was implicated in the aggressiveness and invasiveness of tumor cells through its positive correlation with invasiveness and antiapoptotic molecules, uPAR, bcl-2, and TIMP-1, nuclear phosphorylated β-catenin may be a more sensitive probe for biologically significant activation of tumor cells (21)(22)(23). The current study suggests that Dkk1 regulates phosphorylated β-catenin level in nuclei, which would be correlated with the migration and invasiveness of OSCC cells.…”

“…Nuclear localization of phosphorylated β-catenin may be related to changes at other stages in the signaling pathway (20)(21)(22)(23)40). A high level of nuclear phosphorylated β-catenin was involved in the increased invasiveness phenotype and in the low survival rates of melanoma and breast cancer (20,21). Because nuclear phosphorylated β-catenin was implicated in the aggressiveness and invasiveness of tumor cells through its positive correlation with invasiveness and antiapoptotic molecules, uPAR, bcl-2, and TIMP-1, nuclear phosphorylated β-catenin may be a more sensitive probe for biologically significant activation of tumor cells (21)(22)(23).…”

“…With activation of the Wnt signaling pathway, β-catenin accumulates in the cytoplasm and is translocated into the nucleus and combined with lymphocyte enhancer factor/T-cell factors to activate downstream target genes involved in cancer development (18,19). Previous studies have suggested that high levels of nuclear phosphorylated β-catenin are associated with low survival rates and possibly related to overexpression of several molecules, such as uPAR, bcl-2 and TIMP-1 (20)(21)(22)(23).…”

Prognostic Value of β-catenin Expression in Breast Cancer Patients: a Meta-analysis

“…Alteration of molecular biological markers in tumor tissues has become an important part in predicting the prognosis of patients with BC and seemed more specific than markers currently used in clinical such as TNM stage, weight loss and lymph node metastasis. There are many reports about the prognostic significance of β-catenin in BC (Lin et al, 2000;Gillett et al, 2001;Lim and Lee, 2002;Chung et al, 2004;Dolled-Filhart et al, 2006;Nakopoulou et al, 2006;Park et al, 2007;Fanelli et al, 2008;Paredes et al, 2008;Khramtsov et al, 2010;Kim et al, 2010;Logullo et al, 2010;Lopez-Knowles et al, 2010;Geyer et al, 2011;Cheng et al, 2012;Mukherjee et al, 2012;Xu et al, 2012;Ho et al, 2013;Pang et al, 2013;Weissenbacher et al, 2013;Li et al, 2014). However, results were inconsistent.…”