Abstract 2344: Distinct combinations of signaling pathways promote migration of MDA-MB-231 breast carcinoma cells in response to different stimuli

Abstract

Abstract Cancer cell invasion and metastasis are predicated on the activation of signaling pathways that control dynamic organization of cytoskeletal architecture. The coordinate reorganization of an actin network pushing at the leading edge and an actin-myosin mediated retraction at the rear of the cell facilitates cell polarity to allow directed movement. Motility of the highly invasive breast carcinoma cell line MDA-MB-231 is promoted by various stimuli including lysophosphatidic acid (LPA), hepatocyte growth factor (HGF) and epidermal growth factor (EGF). The goal of this project is to delineate the signaling pathways mediating motility in response to each of these stimuli. Identifying common and conditional pathways mediating cell motility has important implications for therapeutic intervention of cancer cell invasion and metastasis. We conducted migration, invasion, and morphology assays in the presence of inhibitors for pathways known to contribute to the cytoskeletal reorganization required for cell migration. LPA, HGF and EGF were evaluated for their capacity to signal through the Rho family small GTPases, Rho and Rac, the MAP kinase pathway via MEK1/2 and myosin light chain kinase (MLCK) to influence cell migration and invasion. LPA is a recognized component of breast cancer progression and potent stimulator of Rho activity, which has been extensively implicated in the migration of carcinoma cells in a variety of cancers including breast. Surprisingly, LPA-stimulated migration of MDA-MB-231 cells was not affected by Rho inhibitors but was instead sensitive to Rac inhibition. In contrast, Rho was required for HGF and EGF-stimulated migration of MDA-MB-231 cells while Rac had no effect on these processes. Other common pathways mediating cell motility including MLCK are used by all three chemoattractants. MDA-MB-231 cells employed all of the pathways examined for invasion, potentially reflecting the complexity of navigating in a three dimensional environment. These observations suggest that while multiple signaling pathways contribute to the migratory potential of a cancer cell, not all pathways are operating under all conditions. Different context-specific pathways may supplement a core of common pathways to create a functional signal but the characteristics of the response will likely rely on the particular combination used by the cell. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2344. doi:10.1158/1538-7445.AM2011-2344