My lab in interested in signal transduction by tyrosine kinases, with a particular emphasis upon members of the Src family of tyrosine kinases. We primarily work on the receptor for prolactin. Prolactin stimulates the proliferation and differentiation of mammary epithelial cells, and perhaps is best known for stimulating the transcription of milk protein genes. Prolactin also maintains the viability of mammary epithelial cells during lactation by suppressing programmed cell death. We have demonstrated that Src-like kinases are required for activation of mitogenic and anti-apoptotic signaling pathways downstream of both of these receptors. Specifically, Src-like kinases appear to regulate the activation of phosphatidylinositol 3-kinase and the subsequent activation of the anti-apoptotic protein kinase Akt. We are currently determining the mechanism by which Src-like kinases are activated and what intermediates regulate Akt activation. This includes an analysis of mammary gland development in mice that lack expression of specific Src family kinases.
Our interest in Akt has also led us to examine the role of Akt in mammary gland development and tumorigenesis. We have generated transgenic mice that express a constitutively activated mutant of Akt in mammary gland and have demonstrated that Akt significantly delays mammary gland involution, an apoptotic process in which perhaps 80% of mammary epithelial cells die. In addition, it appears that a preneoplatic state is established in these mice which predisposes them to mammary cancer. We are currently characterizing these mice to identify potential substrates for Akt, as well as genes whose transcription maybe regulated by Akt. Future studies will address what oncogenes cooperate with Akt in generating mammary tumors, and whether Akt is activated in human breast cancer.