Abstract P6-01-14: Dissection of the Abl interactor 1 signaling in metastatic breast cancer cells

Abstract

Abstract Abl interactor 1 (Abi1) is a key component of WAVE regulatory complex (WRC) that regulates actin cytoskeleton reorganization, membrane receptor signaling, and intracellular trafficking. Recent in vitro and in vivo studies as well as the studies of human patient samples suggest that Abi1 may play an important role in breast cancer (BC) metastasis. To determine if Abi1 is deregulated in metastatic breast cancer cells, we compared the expression of Abi1 in a panel of human breast cancer cell lines exhibiting distinct metastatic properties. In comparison with low-metastatic ER+/PR+ BC lines MCF-7 and T47D and a non-transforming mammary epithelial cell line MCF-10A, two ER-BC lines CN34 and MDA 231 and their sublines selected by high metastatic potential to bone (231Bo), brain (231Br and CN34Br), and lung (231LM2) show significantly reduced Abi1 protein levels, with greater reduction found in highly metastatic sublines. It is unlikely that the down-regulation of Abi1 expression in these metastatic BC cells occurs at mRNA level, because RT-PCR analysis shows no significant difference in Abi1 mRNA levels among the cells analyzed. Interestingly, despite a reduction in protein level, the tyrosine phosphorylation of Abi1 was increased in CN34, MDA231, and their metastatic sublines compared to low-metastatic BC cells. The tyrosine phosphorylation of Abi1 is stimulated by epidermal growth factor (EGF) in these cells and Abi1 is recruited to EGF receptor (EGFR) upon EGF stimulation. The deregulation of Abi1 in metastatic BC cells is mediated by Abl tyrosine kinases, as the inhibition of Abl family kinases by imatinib not only attenuates EGF-stimulated Abi1 tyrosine phosphorylation but also rescue the down-regulation of Abi1 protein in metastatic BC cells. These findings are consistent with a role of the EGFR-Abl-Abi1 signaling in BC metastasis. The studies suggest that this pathway may serve as a biomarker for diagnosis and/or prognosis of metastatic breast cancer. We have identified the tyrosine 213 in Abi1 as a major phosphorylation site stimulated by Abl kinases and have generated a unique conditional Abi1 depletion/re-expression system to dissect how the deregulation of the Abi1 signaling contributes to BC metastasis. Citation Format: Jiang P, Tang H, Hogan H, Tate S, Ryan W, Paul L, Liu X, Zonghan D. Dissection of the Abl interactor 1 signaling in metastatic breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-01-14.