DACH1 Is a Cell Fate Determination Factor That Inhibits Cyclin D1 and Breast Tumor Growth

Abstract

Obstacles to the expansion of cells with proliferative potential include the induction of cell death, telomerebased senescence, and the pRb and p53 tumor suppressors. Not infrequently, the molecular pathways regulating oncogenesis recapitulate aberrations of processes governing embryogenesis. The genetic network, consisting of the dachshund (dac), eyes absent (eya), eyeless, and sine oculis (so) genes, regulates cell fate determination in metazoans, with dac serving as a cointegrator through a So DNA-binding factor. Here, DACH1 inhibited oncogene-mediated breast oncogenesis, blocking breast cancer epithelial cell DNA synthesis, colony formation, growth in Matrigel, and tumor growth in mice. Genetic deletion studies demonstrated a requirement for cyclin D1 in DACH1-mediated inhibition of DNA synthesis. DACH1 repressed cyclin D1 through a novel mechanism via a c-Jun DNA-binding partner, requiring the DACH1 ␣-helical DS domain which recruits corepressors to the local chromatin. Analysis of over 2,000 patients demonstrated increased nuclear DACH1 expression correlated inversely with cellular mitosis and predicted improved breast cancer patient survival. The cell fate determination factor, DACH1, arrests breast tumor proliferation and growth in vivo providing a new mechanistic and potential therapeutic insight into this common disease.

Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells

“…As far as we know, this is the first study showing loss of DACH1 gene function in tumor cells at the genomic level. Our observation supports recent studies indicating that DACH1 scarcely expressed in tumor-initiating cells and such low expression correlated with poor prognosis of breast cancers (17,18,47). We showed that DACH1 expression decreases proliferation of glioma cells and suppresses tumorigenicity through inhibition of bFGF-dependent spheroid formation.…”

“…The chromosomal losses were found at least in 11 samples (GBM case 1,3,4,5,18,19,24,25,26,27, and 28; 39.3%), and three of them (GBM case 4, 5, and 27; 10.7% of GBMs) displayed homozygous deletion (Fig. 1B and Fig.…”

“…DACH1 is structurally related to c-Ski and SnoN, which act as transcriptional repressors of the transforming growth factor-β (TGF-β) signaling pathway through the interaction with Smad proteins (16). Previous studies showed that human DACH1 inhibited TGF-β signaling through repressing cyclin D1 (CCND1) expression and decreased proliferation of breast cancer cells (17,18). We examined whether DACH1 expression affected TGF-β signaling in glioma cells.…”

Nuclear Factor-κB Enhances ErbB2-Induced Mammary Tumorigenesis and Neoangiogenesis in Vivo

“…NAFA cells grew as complex multiacinar structures with a disorganized architecture ( Figure 4C, top), resembling the morphology of MCF10A cells transduced with ErbB2. 33 NAFA cells transduced with I B␣SR, however, grew as spheroids in 3D Matrigel resembling nontransformed murine mammary epithelium ( Figure 4C, bottom). 38 The mean volume of MCF10A/ErbB2* and NAFA cell acini grown in 3D Matrigel for 12 days was reduced by …”

“…The colony size and morphology were monitored and photodocumented as previously described. 33 Western blot analysis was conducted using antibodies to p65 (Rockland Immunochemicals Inc., Gilbertsville, PA), p50 (Upstate, Lake Placid, NY), phosphorylated p65 (93H1; Cell Signaling, Danvers, MA), Akt1 (2H10, Cell Signaling), phosphorylated Akt1 (S473, Cell Signaling), phosphorylated Erk (E-4, Santa Cruz Biotechnology, Santa Cruz, CA), Erk1 (C-16, Santa Cruz Biotechnology), Erk2 (C-14, Santa Cruz Biotechnology), FLAG (C-21, Santa Cruz Biotechnology), I B␣ (C19, Santa Cruz Biotechnology), and the loading control guanine dissociation inhibitor (GDI), or ␤-actin (Upstate).…”