Abstract 3964: Transforming growth factor-beta dependent regulation in breast cancer progression

Abstract Transforming growth factor-ß (TGF-ß) has a wide range of biologic functions such as the regulation of cell growth, differentiation, and immunologic response in various types of cells. The involvement of TGF-ß in the pathogenesis of breast cancer has been proposed based on its capacity to stimulate the production of extracellular matrix (ECM) proteins and to regulate their metabolism. Induction of plasminogen activator inhibitor-1 (PAI-1) by TGF-ß may contribute to the degradation of extracellular matrix during cancer invasion by decreasing the adhesive strength of cells. Thus, it is important to clarify the mechanism of TGF-ß-induced PAI-1 production. Several polymorphisms have been described in the PAI-1 gene. We examined the influence of the G/A (−844) and 4G/5G (−675) polymorphisms in the promoter region on TGFß-induced PAI-1 expression by breast cancer cells (MDA-MB231, MCF7). The genotype of breast cancer cells was identified by sequencing. TGF-ß-induced PAI-1 mRNA expression was determined by real time polymerase chain reaction (PCR). Activation of MAPKs and Smad proteins was evaluated by an immunoblot analysis. The activities of PAI-1 promoter were measured by a luciferase reporter assay. TGF-ß increased PAI-1 expression in a genotype-dependent manner, higher values observed for MDA-MB231 (4G/4G, A/A) compared with MCF7 (5G/5G, G/G). These results suggest that regulation by TGF-ß influences the PAI-1 polymorphism-dependent expression in breast cancer cells. Analysis of PAI-1 genotype may help identifying subgroups of breast cancer risk. 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 3964.</jats:p