Abstract LB-218: S100A9 is a novel biomarker for poor survival of breast cancer patients
Authors: Noetzel Erik , Schütz Anke , Bernhagen Jürgen , Hartmann Arndt , Dahl Edgar , Knüchel-Clarke Ruth 
Published: February 2011

Abstract
Introduction: S100A9 (Calgranulin B) is a pro-inflammatory cytokine found to be up-regulated under cellular stress conditions, for instance inflammatory disorders. Furthermore, S100A9 overexpression has been detected in squamous, skin, lung, prostate and colorectal cancer. Regarding human breast cancer, S100A9 protein expression in epithelial tumor cells is supposed to be associated with advanced tumor stage. In the present study we aimed to investigate the predictive biomarker quality of S100A9 in human breast cancer. In addition, we analyzed the functional relationship between S100A9 expression and macrophage migration inhibitory factor (MIF) signaling. MIF is a mediator of acute and chronic inflammatory processes and is upregulated in human breast cancer, where it is supposed to play a pro-oncogenic role.
Material and Methods: Using immunohistochemistry we systematically analyzed S100A9 expression in invasive breast carcinomas (n=182) and normal breast tissues (n=45). Staining was quantified using the immunoreactive score (IRS) according to Remmele and Stegner. The S100A9 mRNA level in the human breast cancer cell line MDA-MB468, before and after MIF protein stimulation (150ng/ml), was measured by real time PCR. Statistical data evaluation was done with SPSS17.0.
Results: Cytosolic S100A9 protein expression was present in 35% (mean IRS=3.3 standard deviation (±) 0.38, range=1-12) of breast carcinomas, whereas only 11% of normal breast tissue showed marginal S100A9 staining (mean IRS=1.2 ±0.2, range=1-2) (P=0.0042). S100A9 expression in tumor cells was significantly associated with poor tumor differentiation (P&lt;0.0001), advanced tumor size (P=0.0033), negative estrogen receptor (P=0.0022) and progesterone receptor status (P&lt;0.0001). Univariate overall survival analysis demonstrated a highly significant correlation (P=0.0008) between S100A9 expression and unfavorable prognosis. Multivariate Cox regression analysis deciphered an increased risk for tumor related death of breast cancer patients in case of S100A9 expression (HR=2.1, P=0.024). In addition, we found significantly increased S100A9 mRNA expression levels (P=0.018) after in vitro stimulation of MDA-MB468 breast cancer cells with recombinant MIF for 6h (188%) and 24h (240%), respectively.
Conclusion: We show that tumor related S100A9 expression is associated with poor patient survival and advanced tumor stages, in agreement with its close correlation to tumor size, grading, and negative hormone receptor status. Thus, S100A9 protein expression could serve as a new predictive biomarker for human breast cancer. Furthermore, we demonstrate that S100A9 could be a novel target of MIF-signaling. Hence S100A9 may be linked to inflammation related carcinogenesis. In summary, our data indicate that S100A9 expression may contribute to breast cancer progression, possibly in the context of inflammatory pathways fueling cancer development.
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 LB-218.