Abstract 1024: Tumor suppressive effects of S100A7 are mediated through β-catenin/TCF4 pathway in ERα positive breast cancer
Authors: Yadwinder S. Deol, Mohd W. Nasser, Ramesh Ganju
Journal: Cancer Research (2011)

Abstract Background: Psoriasin (S100A7) is a low molecular weight protein associated with several epithelial malignancies including psoriasis, breast cancer, oral squamous cell carcinoma, etc. It is highly expressed in ductal carcinoma in situ and is mainly associated with the worst prognosis in invasive estrogen receptor α negative (ERα−) breast cancers; however, its exact role in ERα positive (ERα+) breast cancers is not known. Therefore, we investigated the tumorigenic potential of S100A7 over expression in ERα+ breast cancer cells both in vitro and in vivo. Methods: The tumorigenicity of stably over-expressing S100A7 and vector control ERα+ cell lines was assessed using proliferation, migration and wound healing assays. Microarray analysis was carried out to determine the tumorigenic mechanisms associated with S100A7 over-expression and the validation of the targets was performed using real time PCR and immunoblotting. In vivo effect of S100A7 over-expression on tumorigenicity was analyzed using xenograft mouse models and the tumors derived from these mice were analyzed using immunohistochemistry. Results: S100A7 over-expressing ERα+ cells showed significantly reduced EGF-induced proliferation, migration and wound healing compared to vector control cells. Characterization of the EGF-mediated signaling pathways revealed reduced phosphorylation of EGFR, AKT and ERK in S100A7 over-expressing cells. We also observed decreased mRNA and protein levels of β-catenin pathway associated genes -TCF4 and cyclinD1 in S100A7 over-expressing cells. Further analysis of β-catenin /TCF4 pathway showed reduced expression of β-catenin and increased expression of GSK3β and phospho β-catenin in S100A7 over-expressing cells. In addition, we found decreased expression of c-myc and cyclin D1 which are downstream targets of β-catenin/TCF4 pathway. Next, we observed enhanced interaction of E-cadherin and β-catenin in the membranes of S100A7 over-expressing cells. We also observed decreased Rac activation and actin polymerization in S100A7 over-expressing cells which may account for their reduced migration. Finally, we demonstrated that S100A7 over-expressing cells decreased tumor formation in nude mouse model. Furthermore, the immunohistochemical analysis showed down regulation of Cyclin D1 and β-catenin and increased expression of E-cadherin in S100A7 over-expressing tumors, thus confirming the reduced activation of β-catenin/TCF4 pathway in vivo. Conclusions: We conclude that S100A7 decreases the tumorigenicity of ERα+ cells by down modulating β-catenin/TCF4 pathway both in vitro and in vivo. S100A7 is normally associated with increased tumorigenicity in ERα− breast cancer but our results suggest that S100A7 may have a differential role in ERα+ and ERα− cells. Our studies indicate that S100A7 could act as a novel therapeutic target for drug resistant ERα+ breast tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1024. doi:10.1158/1538-7445.AM2011-1024