Wnt Signalling Pathway Activation Plays Important Role in the Oncogenesis of TNBC and Is Associated with Poor Survival Outcome
Jabed Iqbal, Aye A Thike, Syed S Ahmed, Puay Hoon Tan. Singapore General Hospital, Singapore, 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 the oncogenesis of invasive breast carcinomas via inappropriate activation of the Wnt/beta-catenin signalling. Secreted frizzled-related protein 1 (SFRP1), a tumor suppressor which antagonizes this pathway is frequently lost in breast tumors. The goal of this study was to investigate the expression of sFRP1 and related downstream proteins in TNBC.
Design: Immunohistochemistry was performed on paraffin-embedded tumor tissue of a consecutive cohort of 640 female patients with TNBC diagnosed between 2001 to 2008. Antibodies to sFRP1, beta-catenin, cyclin D1 and E-cadherin 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 and E-cadherin expression with clinicopathological parameters, DFS and OS were evaluated using H-score. A p value of <0.05 defined statistical significance.
Results: Loss of sFRP1 (89%) was seen in majority of cases with increased expression of cyclin D1 (77%) associated with aberrant (nuclear/cytoplasmic) expression of beta-catenin (48%). Loss of sFRP1, cyclin D1 over expression and aberrant beta-catenin staining was associated with basal-like breast cancer. Loss of sFRP1 signals poor overall survival and was associated with nuclear grade and nodal status. Loss of both sFRP1 and E-cadherin expression was correlated with aberrant beta-catenin expression (p=0.001). Significantly, nuclear beta-catenin expression was associated with poor OS and reduced E-cadherin expression.
Conclusions: These results show that (1) sFRP1 loss is significant in TNBC (2) its suppression leads to oncogenic activation of WNT signalling pathway via aberrant expression of beta-catenin (3) sFRP1 and its downstream molecules beta-catenin and cyclin D1 may be used as prognostic markers to predict poor survival in a subgroup of TNBC. Due to ubiquitous involvement of beta-catenin in multiple cell signalling pathways it can be a surrogate target for new chemotherapeutic molecules in TNBC.
Tuesday, March 5, 2013 11:00 AM
Proffered Papers: Section B, Tuesday Morning