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Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8.

Research paper by Kongming K Wu, Sanjay S Katiyar, Anping A Li, Manran M Liu, Xiaoming X Ju, Vladimir M VM Popov, Xuanmao X Jiao, Michael P MP Lisanti, Antonella A Casola, Richard G RG Pestell

Indexed on: 10 May '08Published on: 10 May '08Published in: PNAS



Abstract

Oncogene-mediated signaling to the host environment induces a subset of cytokines and chemokines. The Drosophila Dac gene promotes migration of the morphogenetic furrow during eye development. Expression of the cell-fate determination factor Dachshund (DACH1) was lost in poor prognosis invasive breast cancer. Mouse embryo fibroblasts derived from Dach1(-/-) mice demonstrated endogenous Dach1 constitutively represses cellular migration. DACH1 inhibited cellular migration and invasion of oncogene (Ras, Myc, ErbB2, c-Raf)-transformed human breast epithelial cells. An unbiased proteomic analysis identified and immunoneutralizing antibody and reconstitution experiments demonstrated IL-8 is a critical target of DACH1 mediating breast cancer cellular migration and metastasis in vivo. DACH1 bound the endogenous IL-8 promoter in ChIP assays and repressed the IL-8 promoter through the AP-1 and NF-kappaB binding sites. Collectively, our data identify a pathway by which an endogenous cell-fate determination factor blocks oncogene-dependent tumor metastasis via a key heterotypic mediator.

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