Abstract A8: Fibulin-5 (FBLN5) initiates EMT and induces MMPs expression via β1 integrin/EGFR/ERK pathway

Abstract

Abstract Epithelial-mesenchymal transition (EMT) is a normal physiological process that regulates tissue development, remodeling and repair; however, aberrant EMT also elicits disease development in humans, including lung fibrosis, rheumatoid arthritis and cancer cell metastasis. Transforming growth factor-β (TGF-β) is a master regulator of EMT in normal mammary epithelial cells (MECs), wherein this pleiotropic cytokine also functions as a potent suppressor of mammary tumorigenesis. In contrast, malignant MECs typically become resistance to TGF-β-mediated cytostasis and develop the ability to proliferate, invade and metastasize when stimulated by TGF-beta. Therefore, the understanding of how TGF-β promotes EMT may offer new insights into targeting the oncogenic activities of TGF-β in human breast cancers. Previously, we showed that the TGF-β gene target, FBLN5, initiates EMT and enhances that induced by TGF-β. FBLN5 stimulated matrix metalloproteinase (MMP 2,3, and 9) expression and activity, leading to MEC invasion and EMT. While WT FBLN5 induces EMT and MMP expression, RGE mutant (loss of integrin binding activity) of FBLN5 fails to induce EMT and MMP expression. We show here that FBLN5 induces EGFR expression, and the inhibition of EGFR and ERK1/2 MAPK with AG 1478 β3 integrin suppresses FBLN5 induced MMP expression, the expression of D119A mutant β3 integrin fails to suppress FBLN5-induced MMP expression. In addition, knock-down of β1 integrin reverses FBLN5-induced EMT and suppress FBLN5-induced MMPs expression. These results suggest FBLN5 induces EMT and MMP expression in β1 integrin-dependent β1 integrin/EGFR/ERK signaling pathway in MECs. These findings identify a novel EMT and tumor-promoting function for FBLN5 in developing and progressing breast cancers. Citation Format: Yonghun Lee, William P. Schiemann. Fibulin-5 (FBLN5) initiates EMT and induces MMPs expression via β1 integrin/EGFR/ERK pathway. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A8.