Abstract
Abstract Purpose of Study: Psoriasin (S100A7) is a small 11 kDa calcium binding protein which is highly expressed in invasive breast carcinomas and high grade ductal carcinoma in situ. It has also been shown to be associated with ER-α negative phenotypes. However, not much is known about how S100A7 regulates tumor growth and metastasis in ER-α negative breast tumors. Here we elucidate S100A7-mediated effects in breast tumorogenesis. Methods: We studied EGF and IGF-mediated cell migration and cell motility in vitro in S100A7 overexpressing MDA-MB-231 cells by standard assays. For in vivo metastasis, luciferase positive MDA-MB-231-S100A7 or vector cells were injected intracardially in mice and monitored weekly by bioluminescence imaging (BLI). To study the role of S100A7 in mammary tumorogenesis, we generated MMTV-rtTA/S100A7/A15 transgenic mice which expressed S100A7/A15 in mammary glands under doxycycline induction (1g/kg). Mammary glands were isolated and stained for carmine, H&E and immunostaining according to the standard protocols. Results: We have observed significant increase in EGF-induced migration and wound healing of MB-231-S100A7 compared to vector control. This effect on cell migration/motility was further associated with sustained EGF-induced phosphorylation of EGFR, AKT and ERK. Furthermore, we observed that IGF-1-induced cell migration, cell motility and cell proliferation were significantly enhanced in MB-231-S100A7 cells relative to control. We have also shown that IGF/IGFR-mediated signaling is enhanced in MB-231-S100A7 cells. Furthermore, microarray analysis of MB-231-S100A7cells showed enhanced expression of several target genes involved in metastasis such as MMPs and cell cycle-associated genes. We confirmed the expression of these genes in MB-231-S100A7 cells by Western blot analysis. Since S100A7 has Jab-1 binding site, we studied the effect of IGF or EGF on Jab-1, EGFR and IGFR association. We observed enhanced association of EGFR/IGFR with Jab-1 in MB-231-S100A7 cells compared to control. In in vivo mouse model system, we observed enhanced metastasis in mice injected with luc-MB-231-S100A7 cells, compared to vector controls. To further investigate the role of S100A7 in mammary tumorigenesis, we used MMTV-rtTA/S100A7/A15 transgenic mouse model system. We observed significant increase in mammary hyperplasia in doxycycline-induced mice compared to uninduced group. Conclusion: These data suggest that S100A7 plays a major role in breast cancer progression as well as metastasis that is likely mediated by its association with Jab-1. Further, S100A7/A15 plays a role in initiation and progression of mammary tumorogenesis. Thus, interference with S100A7 functions may provide a novel approach for the treatment of breast cancer. 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 3949.
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