Figure 8: Effect of TGF-β-RI inhibition on DTC burden.

(a) Prevalence of HEp3 DTCs (%) per mouse in control (n = 20) and LY-364947-treated (n = 32) animals (2 independent experiments). (b) Alu qPCR quantification of HEp3 DTCs in BM of mice treated either with dimethylsulphoxide or with LY-364947 10 mg kg⁻¹ every 48 h for 2 weeks. Graph: mean±s.e.m. of Alu amplification signal normalized to mice GAPDH (n = 6 DNA samples from 6 different BM samples were assessed over 2 independent experiments), *P<0.05 by Mann–Whitney test. (c) Fluorescence micrographs of HEp3–GFP DTCs in mouse lungs, 2 weeks after control (scale bar, 80 μm) and LY-364947 treatment (scale bar, 120 μm). Lower graph: quantification of HEp3–GFP DTCs in lungs of control and LY-364947-treated animals. n = 4 mice per condition, *P<0.05 by Mann–Whitney Test. (d) Scheme of the proposed mechanism for TGF-β2-induced dormancy. Binding of TGF-β2 to TGF-β-RIII recruits TGF-β-RII and TGF-β-RI into the complex and activates TGF-β2 signalling, which in turn activates Smad1/5 and induces p27. In addition, TGF-β2 also activates p38α in a TGF-β-RIII-independent manner. In response to TGF-β2, p38α activates SMAD2 and DEC2, which induces p27 and inhibits CDK4. All of these signals integrate and contribute to TGF-β2 induction of quiescence.