Abstract 1174: Mechanisms of Fn14 overexpression in invasive breast tumors

Abstract

Abstract The fibroblast growth factor-inducible 14 (Fn14) signaling axis plays an important role in the regulation of breast cancer cell invasion. Breast tumors express Fn14 whereas normal mammary epithelium does not, and Fn14 expression correlates with poor prognostic indicators. The molecular mechanisms driving aberrant Fn14 expression in breast cancer have not yet been determined. This investigation aims to elucidate the mechanisms underlying Fn14 over-expression. Soluble tumor necrosis factor-like weak inducer of apoptosis (TWEAK), the cognate ligand for Fn14, was found to induce Fn14 expression in some breast cancer cell lines via a proposed autoregulatory mechanism. We also provide evidence to support the likelihood that membrane-bound TWEAK can stimulate Fn14 expression through adjacent tumor-cell interaction. EGF and a variety of other receptor tyrosine kinase ligands known to play a role in breast tumor progression stimulated de novo Fn14 expression in a panel of breast cancer cell lines. We therefore hypothesized that Fn14 expression may be induced by aberrant activation of the MAPK signaling pathway. Using an MCF7 model of TPA-mediated MAPK pathway activation and in vitro invasion using Matrigel-coated Transwell Boyden chambers, we observed TPA-mediated expression of Fn14 concomitant with a dramatic increase in cell invasion. Fn14 expression and invasion in this model were abrogated in the presence of U0126, a specific inhibitor of Mek1/2, implicating a role for MAPK signaling in regulation of Fn14 expression. From previously published microarray-based surveys of genomic aberrations in breast cancer, we also hypothesized that constitutive Fn14 expression may be due to Fn14 gene amplification. We performed fluorescence in situ hybridization analysis of 53 breast tumors and identified 15/53 (28%) tumors with additional copies of Fn14 relative to centromere 16. Fn14 was not amplified in normal breast epithelium or in Fn14-negative cell lines. We conclude that deregulation of Fn14 expression can occur through diverse molecular mechanisms associated with breast tumor progression. A more complete definition of the spectrum of molecular aberrations leading to induction of Fn14 expression in breast cancer requires further studies. 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 1174.