a pathway by which an endogenous cell-fate determination factor blocks oncogene-dependent tumor metastasis

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

Kongming Wu....


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-B 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.

Full text..