The Stat3 paradox: a killer and an oncogene.

Stat proteins regulate many aspects of mammary gland development, including the profound changes that occur during pregnancy, lactation and involution. Stat3 induces transcriptional activation of genes involved in the inflammatory response, and in seemingly contradictory cellular events such as apoptosis, differentiation and stem cell maintenance. While Stat3 signalling during mammary gland involution induces epithelial cell death, aberrant Stat3 activation is widely implicated in breast tumourigenesis. Specific cytokines may initiate either a Stat3-driven proliferative or death response depending on the cell-type and cell-context specific availability of particular combinations of signals and receptors. The paradoxical functions of Stat3 may also be due to the degree and extent of activation in different circumstances, in addition to paracrine signalling between mammary epithelial cells and the surrounding microenvironment. Deciphering the enigmatic nature of Stat3 in the mammary gland may benefit future therapeutic strategies for inducing cell death in breast tumours.