Role of Beta-Catenin as a Mediator in the sFRP1-Induced Wnt Signaling and Epithelial-to-Mesenchymal Transition in Triple Negative Breast Cancer
Jabed Iqbal, Aye Aye Thike, Puay Hoon Tan, Minn Minn Myent Thu. Singapore General Hospital, Singapore
Background: Triple negative breast cancers (TNBC) are defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and C-erbB2 expression. Oncologic managements options are limited in this group of patients. The Wnt/beta-catenin pathway has been implicated in epithelial-to-mesenchymal transition (EMT);inappropriate activation of the Wnt/beta-catenin signaling leads to the development of several human cancers, including breast cancer. Secreted frizzled-related protein 1 (SFRP1) which antagonizes this pathway is frequently lost in breast tumors. Beta-catenin has been implicated in the sustainment of EMT-associated stem-cell like traits. The goal of this study was to investigate possible interactions of the Wnt signaling pathway and EMT in TNBC.
Design: Immunohistochemistry was performed on paraffin-embedded tumor tissue of a consecutive cohort of 115 female patients with TNBC diagnosed between 2005 to 2007. Antibodies to sFRP1, beta-catenin, cyclin D1, E-cadherin and vimentin were applied to sections cut from tissue microarray blocks, using the streptavidin-biotin method. Intensity and proportion of tumor cells stained were assessed. Follow-up information was obtained from casenotes. Disease free survival (DFS) and overall survival (OS) were defined as time from diagnosis to recurrence or death respectively. Associations between sFRP1, beta-catenin, cyclin D1, E-cadherin and vimentin expression with clinicopathological parameters, DFS and OS were evaluated using H-score. A p value of <0.05 defined statistical significance.
Results: Loss of Ecadherin (61%) and sFRP1 (65%) was seen in majority of cases with increased expression of vimentin (28%) and cyclin D1 (81%) associated with aberrant (cytoplasmic) expression of beta-catenin (82%). Both sFRP1 and E-cadherin loss was correlated with aberrant beta-catenin expression (p=0.001). Significantly, beta-catenin loss was associated with poor DFS. E-cadherin and sFRP1 deficient cases showed poor OS. Similarly, poor OS was seen in cases with vimentin upregulation.
Conclusions: These results show that in TNBC, (1) sFRP1 suppression leads to oncogenic activation of WNT pathway via cytoplasmic accumulation of beta-catenin (2) Beta-catenin is important in the cross-talk between canonical wnt signalling and EMT pathway indicating that loss of sFRP1 modulates EMT pathway, mediated by E-cadherin loss and/or vimentin acquisition. (3) E-cadherin down-regulation appears to be associated with Wnt activation via beta-catenin and may be used as a prognostic marker to predict poor survival in a subgroup of TNBC.
Monday, March 19, 2012 1:00 PM
Poster Session II # 56, Monday Afternoon