Abstract 4971: WBP2: A novel phospho-oncoprotein in estrogen receptor-positive breast cancer

Abstract

Abstract WBP2 (WW-domain Binding Protein 2) was first implicated in breast cancer through our previous phosphoproteomics screen on the MCF10AT xenograft-derived isogenic cell line model of human breast cancer progression, where WBP2 was found to be differentially phosphorylated during breast cancer development. We had also shown it to be an authentic tyrosine phosphorylation target of EGFR signaling. In a follow up study, we found that WBP2 expression was low or undetectable in normal breast epithelial cells but overexpressed in breast cancer progression model as well as multiple breast cancer cells of various subtypes. Therefore, we aimed to investigate the oncogenic role of WBP2 in the growth and progression of human breast cancer through its protein overexpression and tyrosine phosphorylation. We first mapped the EGF-dependent tyrosine phosphorylation sites on WBP2 and identified a member of the Src family of tyrosine kinases as the putative upstream kinase of WBP2. Next, we found that Estrogen (E2) stimulation could similarly induce tyrosine phosphorylation of WBP2 via a crosstalk between EGFR and ER pathways. Subcellular fractionation study revealed a phosphorylation-dependent nuclear entry of WBP2 upon E2 or EGF stimulation. Consistent with the reported role of WBP2 as a coactivator for nuclear hormone receptor (ERα/PR), abrogation of tyrosine phosphorylation on WBP2 significantly impaired the E2-induced ER transactivation through reduced E2/EGF-stimulated nuclear entry of WBP2 and in vivo E2-dependent WBP2-ER interaction. Stable overexpression of wild type and phospho-mimic mutant of WBP2 in ER-positive MCF7 breast cancer cell enhanced its cell proliferation, anchorage-independent growth in soft agar, cell migration and cell invasion in the E2-independent and/or E2-dependent manner. These cellular processes could be inhibited, at least in part, by the phosphorylation-defective mutant of WBP2. Potential mechanisms of WBP2-mediated oncogenic transformation will be presented. Collectively, our findings have uncovered the potential of WBP2 as a novel phospho-oncoprotein in ER+ breast cancer. It is conceivable that WBP2 and/or its tyrosine phosphorylated form could serve as a potential prognostic marker or therapeutic target for human 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 4971.