, Volume 6, Issue 1, pp 67-82

TGF-β Signaling in Mammary Gland Development and Tumorigenesis

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Ligands of the TGF-β superfamily are unique in that they signal through transmembrane receptor serine-threonine kinases, rather than tyrosine kinases. The receptor complex couples to a signal transduction pathway involving a novel family of proteins, the Smads. On phosphorylation, Smads translocate to the nucleus where they modulate transcriptional responses. However, TGF-βs can also activate the mitogen-activated protein kinase (MAPK)4 pathway, and the different biological responses to TGF-β depend to varying degrees on activation of either or both of these two pathways. The Smad pathway is a nexus for cross-talk with other signal transduction pathways and for modulation by many different interacting proteins. Despite compelling evidence that TGF-β has tumor suppressor activity in the mammary gland, neither TGF-β 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-β as tumor suppressor and oncogene.