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Adipocyte Differentiation: Relationship to Breast Cancer
Final rept. 1 Oct 1997-22 Mar 2002
ILLINOIS UNIV AT CHICAGO
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We hypothesize that breast malignant epithelial cells interact with surrounding stroma to provide biochemical and structural support for tumor tissue. Specifically, malignant epithelial cells block the differentiation of surrounding adipose fibroblasts through cytokines. Additional epithelial factors strikingly induce aromatase expression in these undifferentiated fibroblasts via switching aromatase gene promoter use from the physiologically used promoter 1.4 to aberrantly activated promoter II. During this entire grant period, we have accomplished all specific aims. First, we showed that factors secreted by malignant epithelium inhibit diffemtiation of adipose fibroblasts to mature adipocytes. These epithelial factors were identified as TNF and IL- 11. TNF and IL-il suppress essential adipogenic transcription factors CElBPa and PPAR7 in undifferentiated adipose fibroblasts. Since aromatase expression resides only in undifferentiated fibroblasts but not in mature adipocytes, inhibition of differentiation serves to increase aromatase-expressing cells around malignant epithelial cells. As a second hit, malignant epithelium secretes additional factors other than TNF or IL-il to upregulate aromatase expression in adipose fibroblasts. We demonstrated that the transcription factor CEBP3 mediates this malignant epithelial cell effect on adipose fibroblasts. CEBP3 binds to promoter II to activate this pathologic promoter in fibroblasts in tumor tissue. The end result is aromatase overexpression and increased local formation of estrogen in breast cancer.
APPROVED FOR PUBLIC RELEASE