Abstract 3169: HER2 signaling regulates Fn14 receptor expression in breast cancer cells
Authors: Asrani Kaushal V. , Winkles Jeffrey A. 
Published: February 2011

Abstract
Human epidermal growth factor receptor (HER)-2 overexpression occurs in ∼25% of all breast cancers and these cancers are frequently associated with increased metastases and poor survival. The molecular mechanisms underlying HER2 tumorigenesis are complex and multifactorial and a unified mechanism for HER2-mediated transformation has not emerged. However, HER2 requires HER3 to fulfill its oncogenic potential and the HER2-HER3 heterodimer functions as an oncogenic unit eliciting the most powerful mitogenic signal. Heregulin (HRG)-β1 is a natural ligand for HER3 and elicits the formation of potent HER2-HER3 heterodimers. HRG is expressed in ∼30% of breast tumors and is a risk factor for invasive breast cancer, independent of HER2. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a widely expressed cytokine of the tumor necrosis factor (TNF) superfamily that can regulate cell proliferation, migration, survival, differentiation and death. TWEAK acts via binding to fibroblast growth factor-inducible 14 (Fn14), the smallest known member of the TNF receptor superfamily. Fn14 is overexpressed in many human tumors, including breast tumors, where high expression levels strongly correlate with both the invasive HER2+/ER- intrinsic subtype and indicators of poor prognosis (Willis et al., Mol. Cancer Res. 6:725 (2008)). In consideration of this finding, we investigated whether HER2 activation in breast cancer cells could directly induce Fn14 gene expression. We found that transient or stable transfection of MCF-7 cells with a HER2 expression plasmid increased Fn14 protein expression as assayed by both Western blot and FACS analysis. Breast tumor tissue from HER2-transgenic mice also showed increased expression of Fn14, when compared with normal mammary gland. Furthermore, when MCF-7 cells were treated with HRG-β1, Fn14 protein expression was increased in a dose- and time-dependent manner. Both the HER2 overexpression-induced and the HRG-β1-induced increase in Fn14 expression in MCF-7 cells could be blocked by treatment with the small-molecule HER1/2 tyrosine kinase inhibitor lapatinib. Studies are in progress to elucidate the signaling pathways involved in the HER2-mediated increase in Fn14 expression, whether this increase is via a transcriptional or a post-transcriptional mechanism, and whether Fn14 may contribute to the increased proliferation and invasion that is associated with HER2/HER3-activated cells. Finally, since Fn14 and HER2 are frequently co-overexpressed in breast tumors, we hypothesize that Fn14 could be a new therapeutic target for those patients with HER2+ breast cancer that display either intrinsic or acquired resistance to HER2-targeted drugs. Research supported, in part, by Susan G. Komen for the Cure Research Grant KG081095 (JAW).
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 3169.