Influence of Stromal Transforming Growth Factor-Beta Receptor Signaling on Mouse Mammary Neoplasia

摘要

The purpose of this proposal was to determine if loss of TGF-beta signaling in the stroma affects tumor development and to identify TGF-beta regulated genes via custom gene chip microarrays. Our laboratory had developed mice transgenic for a dominant-negative TGF-beta type II receptor driven by the metallothionine promoter whose expression was restricted to the mammary stroma. Transgenic and wild type mice were given pituitary isografts, zinc water and either left untreated or treated with 7,12-dimethylbenz-(a)-anthracene (DMBA). Mice treated with carcinogen did not differ in latency, tumors per mouse, growth rate, or tumor free survival. They did differ with respect to histology, however. Mice not treated with carcinogen had a significantly shorter tumor free survival in addition to differences in tumor type. Mammary gland specific custom gene chip microarrays were produced and screened for genes regulated by TGF-beta. Several genes were identified following microarray analysis yet only approximately 15% were verified to be regulated by TGF-beta. One gene, the platelet derived growth factor receptor alpha (PDGFRalpha), was analyzed in detail. The PDGFRalpha was up-regulated in the mammary glands while down- regulated in the mammary fibroblasts treated with TGF-beta. PDGFRalpha did not regulate branching morphogenesis as PDGF pellets implanted into the mammary gland had no effect.