TGF-beta signaling in mammary gland development and tumorigenesis

Ligands of the TGF-beta superfamily are unique in that they signal through transmembrane receptor serine-threonine kinases, rather than tyrosine kinas es. The receptor complex couples to a signal transduction pathway involving a novel family of proteins, the Smads. On phosphorylation, Smads transloca te to the nucleus where they modulate transcriptional responses. However, T GF-betas can also activate the mitogen-activated protein kinase (MAPK)(4) p athway, and the different biological responses to TGF-beta depend to varyin g degrees on activation of either or both of these two pathways. The Smad p athway is a nexus for cross-talk with other signal transduction pathways an d for modulation by many different interacting proteins. Despite compelling evidence that TGF-beta has tumor suppressor activity in the mammary gland, neither TGF-beta receptors nor Smads are genetically inactivated in human breast cancer, though receptor expression is reduced. Possible reasons are discussed in relation to the dual role of TGF-beta as tumor suppressor and oncogene.