Abstract 1067: FOXD3 is a B-RAFV600E-regulated inhibitor of G1/S progression in melanoma cells

Abstract

Abstract The forkhead box transcription factor FOXD3 is a stemness factor that prevents the production of melanocyte progenitors from the developing neural crest; however, its role in human cancers is not known. Here we demonstrate that FOXD3 levels are up-regulated following attenuation of B-RAF and MEK signaling in mutant B-RAF harboring human melanoma cells. This effect was selective since FOXD3 was not up-regulated following MEK inhibition in wild-type B-RAF melanoma cells and mutant B-RAF thyroid carcinoma cells. Ectopic FOXD3 expression potently inhibited melanoma cell growth without altering mutant B-RAF activation of ERK1/2. Inhibition of cell growth was due to a potent G1 cell cycle arrest that was largely dependent on p53 and, to a lesser extent, its downstream target p21Cip1. These studies demonstrate that FOXD3 is suppressed by B-RAF, uncover a novel role and mechanism for FOXD3 as a negative cell cycle regulator and have implications for the repression of melanocytic lineage cells. 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 1067.