Effects of IGFBP-3 Induction by TGF-BETA in Breast Tumorigenesis

摘要

The goal of this research is to study the role of the antagonistic relationship between two opposing growth signals, IGF and TGF-Beta, in mammary turmorigenesis. We set out to test a hypothesis that the induction of IGFBP-3 by TGF-BETA- in stromal fibroblasts is a mechanism by which TGF-BETA- regulates the growth of breast epithelial cells. To do this, a model cell culture system was established in which the effects of TGF-BETA- through IGFBP-3 could be studied. Our results show that recombinant IGFBP-3 is able to block IGF-induced growth of breast cancer cells, however the effects of secreted IGFBP-3 from fibroblast media are unclear. Growth inhibition does occur, but the presence of other molecules in this system cloud IGFBP-3's contribution. Additionally, we set out to define the mechanisms by which TGF-BETA induces IGFBP-3 in MRC-9 cells. We determined that the gene is regulated by TGF-BETA at the level of transcription, and not through mRNA stability. Analysis of the promoter (-1800 bp) for TGF-BETA regulatory elements, however, showed that TGF-b did not significantly induce IGFBP-3 promoter activity in MRC-9 fibroblasts. Therefore, the location of the TGF- b transciptional reglulatory elements in the IGFBP-3 gene remain unknown.