Abstract
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 invasive breast cancer. S100A7 is mainly associated with the worst prognosis in invasive estrogen receptor (ER) α negative breast cancers, however, its exact role in ERα+ breast cancers is not known. Therefore, we investigated the tumorigenic potential of S100A7 over expression in ERα+ breast cancer cells and elucidated signaling mechanisms through which S100A7 may regulate the proliferation and metastasis in these cells. Methods: The tumorigenicity of stably overexpressing 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 overexpression. Validation of the relevant targets from microarray analysis was performed by immunoblotting and immunofluorescence. Results: S100A7 overexpressing ERα+ cells showed significantly reduced proliferation; EGF induced 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 overexpressing cells. We also observed decreased mRNA and protein levels of β-catenin pathway associated genes -TCF7L2 (TCF4) and cyclinD1 in S100A7 overexpressing 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 overexpressing cells. Phosphorylation of β-catenin in the cytoplasm leads to its ubiquitination and decreased translocation into the nucleus, thereby reducing the transcription of downstream targets. Accordingly, we found decreased protein expression of c-myc and cyclin D1 which are downstream targets of β-catenin/TCF4 pathway. Furthermore, we found increased expression of E-cadherin and decreased expression of vimentin and snail in S100A7 overexpressing cells. These proteins along with β-catenin are known EMT (Epithelial to Mesenchymal) markers and their expression pattern indicates the induction of mesenchymal to epithelial transition (MET) in S100A7 overexpressing ERα+ cells compared to vector control. Conclusions: We conclude that S100A7 decreases the proliferation and metastasis in ERα+ cells by down modulating β-catenin/TCF4 pathway and inducing reverse EMT. 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 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2308.
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