Subtype-specific alterations of the Wnt signaling pathway in breast cancer: clinical and prognostic significance.

ABSTRACT

The aim of the study is to understand the importance of the Wnt/ß-catenin pathway in the development of breast cancer (BC) and its association with different clinicopathological parameters. Alterations (deletion/methylation/expression) of some Wnt/ß-catenin pathway antagonists like APC, SFRP1/2, CDH1 and activator ß-catenin (CTNNB1) were analyzed in primary BC in Indian patients. High frequencies (65-70%) of overall alterations (deletion/methylation) of the antagonists were seen in the BC samples. Also, 99% (156/158) of the samples showed alterations in any one of the genes, indicating the importance of this pathway in the development of this tumor. Co-alterations of these genes were observed in 30% of samples, with significantly high alterations in late-onset (37%) and estrogen receptor (ER)-/progesterone receptor (PR)- (37%) BC compared with early onset (21%) and ER/PR+ (18%) BC samples, respectively. Significantly high (P-value = 0.001-0.02) alterations of APC and CDH1 genes were seen in ER-/PR- BC compared with ER/PR+ BC. Immunohistochemical analysis showed reduced expression of the Wnt antagonists in BC concordant with their molecular alterations. Nuclear localization of ß-catenin showed significant association with alterations in the antagonists and was also significantly high in the ER-/PR- BC samples. Alterations of SFRP2 coupled with a late clinical stage and low/nulliparity predicted the worst prognosis in BC patients. Therefore, the present study suggests that cumulative alterations in more than one Wnt antagonist along with increased nuclear accumulation of ß-catenin play an important role in the development of BC and have significant clinical as well as prognostic importance.