Dominant Negative Mutants of the Estrogen Receptor as Probes of Estrogen Actionand Inhibitors of Breast Cancer Growth

摘要

Estrogen provides one of the most important growth stimulators for breastepithelium. There Is emerging evidence for complex interactions between estrogen and other growth factors that are important for the growth of breast cancer cells. Growth factor signalling pathways stimulate estrogen responsive genes, perhaps via the estrogen receptor. These findings open new opportunities to block breast cancer cell growth using mutant receptors that function as antagonists. In year 1 of this project, we proposed to develop the key components for initiating this project This included: (1) Creation of a series of estrogen receptor (ER) mutants that might function in a dominant negative manner; (2) Create ER and growth factor responsive reporter genes for studies in transfected cells; (3) Begin transient expression studies for examining interactions between growth factor signaling pathways and the ER pathway; (4) Develop cell proliferation assays in response to estrogen; (5) Develop inducible expression vectors to allow creation of stable cell lines that express mutant ERs; (6) Obtain and begin construction of MMTV and whey acidic protein (WAP) expression vectors for targeting mutant ERs in transgenic mice. We have completed each of these goals as outlined in the original proposal.