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Published online on May 8, 2008
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0802085105
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CELL BIOLOGY
Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8

Kongming Wu*, Sanjay Katiyar*, Anping Li*, Manran Liu*, Xiaoming Ju*, Vladimir M. Popov*, Xuanmao Jiao*, Michael P. Lisanti*, Antonella Casola{dagger}, and Richard G. Pestell*,{ddagger},§

*Departments of Cancer Biology and {ddagger}Medical Oncology, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107; and {dagger}Department of Pediatrics, Division of Infectious Disease, University of Texas Medical Branch, Galveston, TX 77555-0366

Communicated by Hilary Koprowski, Thomas Jefferson University, Philadelphia, PA, March 10, 2008 (received for review December 19, 2007)

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-{kappa}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.

DACH1 | metastasis

Footnotes

Author contributions: S.K., A.L., and M.L contributed equally to this work; K.W. designed research; K.W., S.K., A.L., M.L., X. Ju, V.M.P., and X. Jiao performed research; A.C. contributed new reagents/analytic tools; K.W., M.P.L., and R.G.P. analyzed data; and R.G.P. wrote the paper.

The authors declare no conflict of interest.

§To whom correspondence should be addressed. E-mail: annie.mathies{at}kimmelcancercenter.org

© 2008 by The National Academy of Sciences of the USA


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