Expression of the type III TGF-β receptor is negatively regulated by TGF-β

The type III transforming growth factor-beta receptor (TβRIII or betaglycan) is a ubiquitously expressed transforming growth factor-beta (TGF-β) superfamily coreceptor with essential roles in embryonic development. Recent studies have defined a role for TβRIII in the pathogenesis of human cancers, with frequent loss of TβRIII expression at the message and protein level. Mechanisms for the loss of TβRIII expression remain to be fully defined. Advanced human cancers often have elevated circulating levels of TGF-β1. Here, we define a specific role for TGF-β1 in negatively regulating TβRIII at the message level in breast and ovarian cancer models. TGF-β1 decreased TβRIII message and protein levels in ovarian (Ovca420) and breast cancer (MDA-MB-231) cell lines in both a dose- and time-dependent manner. TGF-β1-mediated TβRIII repression is mediated by the type I TGF-β receptor/Smad2/3 pathway as the activin receptor-like kinase 5 (ALK5) inhibitor, SB431542, abrogated this effect, while the expression of constitutively active ALK5 was sufficient to repress TβRIII expression. Mechanistically, TGF-β1 does not affect TβRIII messenger RNA (mRNA) stability, but instead directly regulates the TβRIII promoter. We define alternative promoters for the TGFBR3 gene, a distal and proximal promoter. Although both promoters are active, only the proximal promoter was responsive and negatively regulated by TGF-β1 and constitutively active ALK5. Taken together, these studies define TGF-β1-mediated downregulation of TβRIII mRNA expression through effects on the ALK5/Smad2/3 pathway on the TGFBR3 gene proximal promoter as a potential mechanism for decreased TβRIII expression in human cancers.