Priscilla A. Furth, M.D.
Laboratory of Cancer Genetics and Hormones
Genetic and hormonal factors work together to regulate epithelial cell survival, proliferation and death. The research program in this laboratory utilizes mouse models to identify how specific signaling pathways act during both normal physiology and tumor progression in the mammary gland and in the salivary gland.
The mammary gland research focuses on understanding two interrelated processes: 1) how mammary epithelial cells make the decision to proliferate during development, to survive during lactation, and undergo apoptosis during involution, and 2) how these processes become dysregulated during tumor progression as mammary epithelial cells lose their growth control and become malignant. Work in the laboratory was the first to demonstrate that apoptotic cell death of mammary epithelial cells is primarily mediated through p53-independent pathways. At the present time this finding is being extended by determining the roles of specific gene products which contribute to cancer progression by inhibiting p53-independent apoptosis. We found that bcl-2 over-expression in mammary epithelial cells is able to block bax induced apoptosis and accelerate tumor progression. On the other side, we have determined that stimulation of specific hormonal pathways can accelerate tumor progression by increasing proliferation and introducing genetic instability. This can lead to earlier cancer development even when apoptosis is not inhibited. Taken together, these results show that aberrations in both apoptotic cell death and cell proliferation pathways contribute to accelerated cancer progression. Targeting both pathways may be required for effective cancer therapy. Study of normal mammary gland involution is a second area of investigation. Significantly, my laboratory has demonstrated that the initial stage of mammary epithelial cell death during involution is controlled by local factors related to milk stasis and is not regulated by changes in levels of hormonal factors.
Finally, the laboratory has expanded its investigations of factors controlling tumor progression to the salivary gland. Similar to the mammary gland, salivary epithelial cell growth and function is also regulated by hormonal factors. The interplay between individual growth factors and specific gene products is under investigation.
Recent Publications:
Li M, Liu X, Robinson T, Bar-Peled U, Wagner K-U, Young WS, Hennighausen L, Furth PA 1997 Mammary derived signals activate programmed cell death during the first stage of mammary gland involution. Proceedings National Academy of Science USA 94:3425-3430.
Ewald D, Li M, Efrat S, Auer G, Wall R, Furth PA, Hennighausen L 1996 Time-sensitive reversal of hyperplasia in transgenic mice expressing SV40 T antigen. Science 273:1384-1386.
Li M, Hu J, Heermeier K, Hennighausen L, Furth PA 1996 Expression of a viral oncoprotein during development of the mammary gland alters cell fate and function. Cell Growth & Differentiation 7:3-11.
Li M, Hu J, Heermeier K, Hennighausen L, Furth PA 1996 Apoptosis and remodelling of mammary gland tissue during involution proceeds through p53 independent pathways. Cell Growth & Differentiation 7:13-20.
