P-Cadherin and β-catenin are useful prognostic markers in breast cancer patients; β-catenin interacts with heat shock protein Hsp27

Abstract

The cadherin-catenin proteins have in common with heat shock proteins (HSP) the capacity to bind/interact proteins of other classes. Moreover, there are common molecular pathways that connect the HSP response and the cadherin-catenin protein system. In the present study, we have explored whether in breast cancer the HSP might interact functionally with the cadherin-catenin cell adhesion system. Beta-catenin was immunoprecipitated from breast cancer biopsy samples, and the protein complexes isolated in this way were probed with antibodies against HSP family members. We are thus the first to demonstrate a specific interaction between beta-catenin and Hsp27. However, beta-catenin did not bind Hsp60, Hsp70, Hsp90, gp96, or the endoplasmic reticulum stress response protein CHOP. To confirm the finding of Hsp27-beta-catenin interaction, the 27-kDa immunoprecipitated band was excised from one-dimensional polyacrylamide gel electrophoresis gels and submitted to liquid chromatography-tandem mass spectrometry with electrospray ionization, confirming a role for Hsp27. In addition, beta-catenin interacted with other proteins including heat shock transcription factor 1, P-cadherin, and caveolin-1. In human breast cancer biopsy samples, beta-catenin was coexpressed in the same tumor areas and in the same tumor cells that expressed Hsp27. However, this coexpression was strong when beta-catenin was present in the cytoplasm of the tumor cells and not when beta-catenin was expressed at the cell surface only. Furthermore, murine breast cancer cells transfected with hsp25 showed a redistribution of beta-catenin from the cell membrane to the cytoplasm. When the prognostic significance of cadherin-catenin expression was examined by immunohistochemistry in breast cancer patients (n = 215, follow-up = >10 years), we found that the disease-free survival and overall survival were significantly shorter for patients expressing P-cadherin and for patients showing expression of beta-catenin in the cytoplasm only (not at the cell surface). The interactions of beta-catenin with Hsp27 and with HSF1 may explain some of the molecular pathways that influence tumor cell survival and the clinical significance in the prognosis of the breast cancer patients.

Downregulation of Hsp27 (HSPB1) in MCF-7 human breast cancer cells induces upregulation of PTEN

“…Hsp27 is a molecular chaperone that can interact with other proteins. For example, in human breast cancer tissues and in a rodent breast cancer cell line, Fanelli et al (2008) reported the interaction of β-catenin with Hsp27 and with HSF1, which may explain some of the molecular pathways that affect the prognosis of breast cancer patients. A recent study reported that histone deacetylase HDAC6, transcription factor STAT2 and procaspase-3 were degraded in human cancerous cells displaying genetically decreased levels of Hsp27 suggesting that they are client proteins of Hsp27 (Gibert et al 2012).…”

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

“…However, we still noted that some of the included studies (Lin et al, 2000;Fanelli et al, 2008;Xu et al, 2012;Li et al, 2014) defined either cytoplasm or nucleus as positive β-catenin expression, which made it difficult to explain which part of accumulation of β-catenin played the most important influence on prognosis in BC patients, only to find that positive β-catenin expression by this definition has significant association with OS. This result confirms our conclusion that β-catenin expression in cytoplasm/ nucleus, which is considered to be indicative of Wnt pathway activation, was significantly associated with an unfavorable prognosis in patients with BC.…”

“…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.…”

“…β-catenin expression and/ or localization are often abnormal in human BC (Jonsson et al, 2000;Lin et al, 2000;Ryo et al, 2001;Ozaki et al, 2005;Dolled-Filhart et al, 2006;Hayes et al, 2008). Increased cytoplasmic and nuclear β-catenin levels which is considered to be indicative of Wnt pathway activation (Fanelli et al, 2008;Hayes et al, 2008;Khramtsov et In this meta-analysis, we categorize the β-catenin by subcellular localization. The association of β-catenin expressions in membrane or cytoplasm/nucleus with prognosis in BC is analyzed respectively.…”

“…Tumor cells escaping from the primary tumor is the 1 Chung et al, 2004;Park et al, 2007;Fanelli et al, 2008;Kim et al, 2010;Logullo et al, 2010;Lopez-Knowles et al, 2010;Xu et al, 2012;Ho et al, 2013;Pang et al, 2013). The discrepancies in conclusions may attribute to some of the defects in individual study such as small sample size or low statistical power.…”