Mechanism of Hormonal Regulation of CAD Gene Expression in Human Breast Cancer Cells
Annual summary rept. 1 May 2003-30 Apr 2006
TEXAS A AND M RESEARCH FOUNDATION COLLEGE STATION
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The CAD gene is trifunctional and expresses carbamoylphosphate synthetaseaspartate carbamyltransferasedihydroorotase which are required for pyrimidine biosynthesis. TODD inhibited hormone-induced activation of CAD mRNA levels and pOAD promoter-reporter gene activity in MOF-7 and ZR-75 cells. Using fluorescence resonance energy transfer FRET it was shown that both E2 and TODD enhanced AhR-ER interactions. E2 also induced interactions between ER and Sp1 however cotreatment with TODD abrogated this effect. Results of this study demonstrate a unique model of AhR-ER crosstalk where the liganded AhR inhibits ER-Sp1 interactions and also recruits ER to Ah-responsive gene promoters such as CYP1A1. In addition CAD gene was also used as a model to study the mechanism underlying the crosstalk between ER and PPAR signaling pathways. PPAR ligand PGJ2 inhibited E2-induced OAD gene expression and also down regulated E2-mediated transactivation of CAD gene promoter constructs and this was reversed by PPAR antagonist TOO7 in MOF-7 cells. This suggests a possible inhibitory crosstalk between PPAR and ER signaling pathways in breast cancer cells. In addition, 1,1- Bis3indolyl-1-p-substitutedphenylmethanes containing p-t-butyl DIM-C-pPhtBu and p-phenyl DIM-C-pPhC6H5 groups a new class of PPAR agonists inhibited E2-mediated transactivation of CAD gene promoter constructs however this effect was PPAR-independent.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research