TMIF--A NOVEL GROWTH INHIBITORY FACTOR/BREAST CARCINOMA

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Work in the recent past, especially with TGF-beta has suggested the existence of growth inhibitory actors which elicit a growth inhibitory effect on normal and neoplastic cells. It therefore appears that secretion of growth factors and growth inhibitors concomitant with selective spatial activation offers cells a mechanism to regulate their interactions with other cells and extracellular connective issues which may help explain many events in morphogenesis. In an attempt to determine if growth inhibitory factors exist which might specifically inhibit the growth of breast carcinoma cells, we undertook a study of screening a large number of human cell lines for secretary factors with such inhibitory activity. This resulted in the identification of one human B- lymphoid cell line which was found to secrete a growth inhibitory factor (TMIF-1) which appeared to inhibit the growth of several breast carcinoma cell lines without affecting the growth of several other cell types. This factor appears to be different from TGF-beta or any other known growth inhibitory factor. Preliminary evidence suggests that TMIF-1 is an 80 kda protein which is glycosylated. This research proposal is aimed at the biochemical characterization of this novel factor and molecular cloning of the gene that encodes for this factor. The aims of the proposal are 1. To purify TMIF-1 to homogeneity and obtain partial sequence of the protein factor; 2. To obtain cDNAs which encode for this factor; 3. To produce recombinant TMIF-1; 4. To study the mechanism of action of TMIF- 1; and 5. To test growth inhibitory properties of TMIF-1 in vivo using athymic nude mice implanted with mammary carcinomas. 6. To study the chemopreventive effects of TMIF-1 in female rats treated with methyl nitroso urea (MNU).