Signaling by the TGF-beta receptor complex is tumor suppressive, as it inhibits cell growth and promotes cell differentiation and apoptosis (Shipley et al. 1986, Hannon et al. 1994, Datto et al. 1995, Chen et al. 2002, Azar et al. 2009). TGF-beta signaling is frequently impaired in cancer, mostly through SMAD4 gene deletion or loss-of-function mutations, which are especially frequent in pancreatic cancer (Hahn et al. 1996, Shi et al. 1997, Fleming et al. 2013). Signaling by TGF-beta receptor complex can also be disrupted by loss-of-function mutations in SMAD2 and SMAD3 (Fleming et al. 2013) or loss-of-function mutations in TGFBR2 (TGF-beta receptor II) (Markowitz et al. 1995, Garrigue-Antar et al. 1995, Parsons et al. 1995, Grady et al. 1999) or TGFBR1 (TGF-beta receptor I) (Chen et al. 1998, Chen et al. 2001, Goudie et al. 2011).
In advanced cancer, signaling by TGF-beta may be tumor promoting, as it induces epithelial-to-mesenchymal transition (EMT), thereby increasing invasiveness (Cui et al. 1996, Guasch et al. 2007, reviewed by Heldin et al. 2012).