Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8.
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.
Wu
Kongming
K
Department of Cancer Biology, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.
Katiyar
Sanjay
S
Li
Anping
A
Liu
Manran
M
Ju
Xiaoming
X
Popov
Vladimir M
VM
Jiao
Xuanmao
X
Lisanti
Michael P
MP
Casola
Antonella
A
Pestell
Richard G
RG
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005136:Eye Proteins / Q000737:chemistry / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009857:Oncogenes / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary; D040901:Proteomics; D014945:Wound Healing
C456264:Dach1 protein, mouse; D005136:Eye Proteins; D016209:Interleukin-8