Loss of Dab2 Expression in Breast Cancer Cells Impairs Their Ability to Deplete TGF-[beta] and Induce Tregs Development via TGF-[beta]

Dab2 is a multifunctional adapter protein which is frequently under-expressed in a variety of cancers. It is implicated in many critical functions, including several signaling pathways, cell arrangement, differentiation of stem cells, and receptor endocytosis. Transforming growth factor-[beta] (TGF-[beta]) is a secreted multifunctional protein that controls several developmental processes and pathogenesis of many diseases. It has been documented that Dab2 played an important role in TGF-[beta] receptors endocytosis. Here, we present evidence that re-expression of Dab2 in SK-BR-3 cell partially restored its ability to deplete TGF-[beta] in surrounding medium by normalizing the trafficking of TGF-[beta] receptors. We also demonstrate that the difference in TGF-[beta] depletions produced by Dab2 expression was sufficient to impact on the conversion of naive CD4+ T cells to regulatory T cells (Tregs), and thus inhibited the proliferation of T cells. This work revealed a critical result that breast cancer cell was deficient in Dab2 expression and related receptor endocytosis-mediated TGF-[beta] depletion, which may contribute to the accumulation of TGF-[beta] in tumor microenvironment and the induction of immune tolerance.