Transforming growth factor alpha (TGFalpha) stimulates proliferation of a variety of cell types including breast cancer cells, acting through the epidermal growth factor receptor (EGF-R). Both breast cancer cells and normal mammary epithelial cells are also able to produce TGFalpha. Since this production is stimulated by estrogens, TGFalpha has been hypothesized to act as an autocrine mediator of estrogen action; its overproduction may thus circumvent normal estrogen dependence and be a step toward hyperproliferative or malignant growth of mammary tissue. Blocking TGFalpha production or action might then prevent or reverse these growth changes. In this project we propose the following specific aims: (1) To continue investigating whether TGFalpha is an autocrine mediator of estrogen-induced growth in breast cancer cells. We will inhibit TGFalpha and/or EGF-R synthesis in human breast cancer cell lines by using stable transfectants expressing inducible antisense TGFalpha or EGF-R mRNAs, or by administering antisense oligonucleotides. This inhibition should block estrogen-induced growth if any TGFalpha autocrine pathway -- intracrine or juxtacrine as well as extracrine -- is important. (2) To determine the importance of the TGFalpha/EGF-R pathway in the induction of benign proliferative and malignant changes in mammary tissue, by examining such changes in transgenic mice carrying TGFalpha and/or EGF-R genes under an MMTV promoter. We will also investigate secondary events necessary for the transformation from the benign hyperproliferative stage to the malignant phenotype, including increased expression of EGF-R in TGFalpha transgenics, increased expression of other known mammary oncogenes known to be expressed in some mouse mammary tumors, or alterations or deletions in two tumor suppressor genes, Rb and P53, known to be associated with mammary tumorigenesis. (3) To explore strategies for inhibiting malignant progression in these transgenic mice overexpressing TGFalpha and EGF-R in mammary tissue. We will specifically investigate receptor tyrosine kinase inhibitors (tyrphostins), active immunization against TGFalpha, antiestrogen therapy, and co-expression of the Rb tumor suppressor gene known to be inactivated in some human breast cancers. These studies will provide important new information on the mechanisms of breast cancer development and progression, as well as suggesting new clinical strategies for prevention and treatment.
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