Analysis of the Regulation of Expression of Transforming Growth Factor-Beta in Human Breast Cancer Cells
Final rept. 1 Oct 1994-30 Aug 1999
DARTMOUTH COLL HANOVER NH
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This combined final report for the research and career development grants relates to three objectives. Work on the first objective first focused on an analysis of the importance of TGF-beta expression as a determinant of clinical outcome. No such correlation was evident. Subsequent experiments examined the importance of a functionally intact TGF-beta signaling pathway with regards to tumor necrosis factor TNF-mediated cytotoxicity of MCF-7 cells, and documented that derepression of Bcl-2 expression as a consequence of loss of TGF-beta responsiveness likely underlies the acquired resistance to TNF. The second objective centered around an in vivo model of tumorigenicity and metastatic potential of breast cancer cells altered with regard to their production of and responsiveness to TGF-beta. Distinct paracrine and autocrine roles for TGF-beta were highlighted, with local invasiveness determined to be largely a paracrine effect of TGF-beta. The most rapid tumor growth was evident with the cells that remained responsive to TGF-beta however. The third onjective was to identify the molecular determinants of promoter usage for TCF-beta3 in breast cancer cell lines. Hypomethylation at a small grouping of CpGs in breast cancer cells was identified as a molecular correlate of downstream promoter activation.
- Anatomy and Physiology
- Medicine and Medical Research