Abstract 3427: A core invasiveness gene signature reveals reduced EMT in samples from patients with IBC, potentially regulated by decreased EGFR- and TGFb-signaling

Abstract

Abstract Introduction. We identified a core invasiveness gene (CIG) signature that predicts the invasive properties of breast cancer cell lines. In the current study, we investigate the translational utility of the current gene signature in human breast cancer, including inflammatory breast cancer (IBC). The latter is a highly invasive and metastatic breast cancer subtype. Materials and methods. Six publicly available gene expression data sets and a data set on 137 IBC and 252 non-IBC samples were analyzed. Each sample was classified according to sets of stromal (N=2), prognostic (N=2), stem cell (N=3), epithelial-to-mesenchymal transition (EMT) (N=3) and pathway (N=20) gene signatures. In addition, the cell-of-origin subtype classifier and our own CIG-signature were applied. Associations between the CIG-signature and clinicopathological or molecular features were searched for using univariate and multivariate analysis. Results. We identified associations of the CIG signature (FDR<0.01) with a mammosphere-derived classifier (median Rs=0.49) and with two EMT-signatures (Core-EMT: median Rs=0.52; EMT/stromal classifier: median Rs=0.59). In addition EGFR, STAT3 and TGFb were found to be hyperactivated in CIG-positive tumors (median Rs=0.45; 0.33 and 0.60 respectively). No relations between CIG-expression and stromal gene expression, molecular subtypes or any of the clinicopathological variables were observed. Compared to non-IBC, decreased CIG-expression, TGFb- and EGFR-activation were observed in IBC (respectively P<0.0001, P<0.0001 and P=0.036). As for other EMT-associated gene signatures, both positive (Claudin-low and LYN-signatures: P=0.004 and P=0.015) and negative (EMT/stromal classifier: P=0.015) associations with IBC have been observed. When testing the core-EMT signature, no difference was found (P=0.166). Discussion. We show that the CIG signature in breast cancer is correlated with EMT, stem cell biology and EGFR-, TGFb- and STAT3-activation. Samples from patients with IBC demonstrate ambiguous EMT-patterns, suggest that tumor cells from patients with IBC are in a specific state of cell plasticity and EMT as such is not the main mode of invasion in IBC. On the contrary, lowered TGFb signaling in IBC suggest a form of collective invasion. 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 3427. doi:10.1158/1538-7445.AM2011-3427