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 ⁄ b-catenin pathway in the development of breast cancer (BC) and its association with different clinicopathological parameters. Alterations (deletion ⁄ methylation ⁄ expression) of some Wnt ⁄ b-catenin pathway antagonists like APC, SFRP1 ⁄ 2, CDH1 and activator b-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 b-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 b-catenin play an important role in the development of BC and have significant clinical as well as prognostic importance. (Cancer Sci 2012; 103: 210-220) B reast cancer (BC) is a frequently occurring cancer in women worldwide and accounts for 25% of cancer cases in the Eastern Indian population, especially in urban areas.(1) There are several known risk factors for BC.(2) In general, younger women with BC (age £ 40 years) exhibit more aggressive pathological features and lower survival rates compared with older women with BC.(3) The molecular subtypes of BC, which usually lack expression of the estrogen receptor (ER) and progesterone receptor (PR), also show the worst prognosis of BC.(4) It has been suggested that ER and PR play important roles in regulating the mammary stem cell population and its development. The stem cell population is regulated by a number of selfrenewal pathways, (6) among which the Wnt ⁄ b-catenin pathway is quite important due to its cross-talk with the ER signaling pathway (7) and its alterations in several carcinomas including BC. (8) There are several antagonists of the Wnt ⁄ b-catenin pathway like SFRP1, SFRP2, APC and CDH1.(9,10) In different ways, these antagonists regulate the cytoplasmic and nuclear accumulation of b-catenin, the signal transducer of this pathway. (8,11) Accumulation of data shows varying frequencies of deletion (23-73%) and frequent promoter methylation in the Wnt antag...

microRNA-29 negatively regulates EMT regulator N-myc interactor in breast cancer

“…Breast cancer lacks classical Wnt activating mutations (such as APC) that are seen in colon cancer. However, aberrant Wnt response in the form of nuclear β-catenin is frequently observed in breast cancer [44–47]. In the tumor microenvironment Wnt ligands are known to be present.…”

Expression of WNT genes in cervical cancer-derived cells: Implication of WNT7A in cell proliferation and migration

“…Especially, WNT10A and WNT7A expression was found strongly downregulated (À 9.31 and À 5.34, respectively) in HeLa and SiHa cells, suggesting that alterations in these ligands could be important for carcinogenesis. Validation of all WNT ligand expression was performed by qPCR (data not shown); however, because WNT7A has been previously described as being involved in ovarian, breast, and lung cancer [11,16,26], and also because our group detected its expression in primary foreskin-derived cells, we delved deeply into the role of WNT7A in the CC model.…”

“…WNT pathway ligands have been classified into two groups: those that can induce the canonical pathway, and those that can activate the non-canonical pathways. Aberrant expression of WNT ligands has been implicated in numerous types of cancer, not only in leukemia, breast, gastrointestinal, and lung [10][11][12][13], but also in CC [14].…”

Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer

“…There is ample evidence that Wnt signaling in the breast drives tumor cell growth and invasiveness [12] and clinical data supports this with correlations between genetic alterations in Wnt signaling pathway molecules and patient prognosis [13]; however, the role of Wnt signaling in promoting cancer cell growth in bone has not been explored.…”