The cyclin D1 gene is overexpressed in human breast cancers and is required for oncogene-induced tumorigenesis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPARγ induces hepatic steatosis, and ligand-bound PPARγ promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPARγ function, transactivation, expression, and promoter activity. PPARγ transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB- and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix (HLH) structure. The cyclin D1 HLH region was also required for repression of the PPARγ ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPARγ-specific ligands (BRL49653, troglitazone) was enhanced in cyclin D1-/- fibroblasts and reversed by retroviral expression of cyclin D1. Homozygous deletion of the cyclin D1 gene, enhanced expression by PPARγ ligands of PPARγ and PPARγ-responsive genes, and the liver of cyclin D1-/- mice displays the features of hepatic steatosis consistent with increased PPARγ activity. Reduction of cyclin D1 abundance in vivo using ponasterone-inducible cyclin D1 antisense transgenic mice, increased expression of PPARγ. The inhibition of PPARγ function by cyclin D1 is a new mechanism of signal transduction cross-talk between PPARγ ligands and mitogenic signals that induce cyclin D1. Reduction in PPARγ expression together with the increase in Cyclin D1 may represent a key genetic alteration underlying the transition from normal breast tissue to breast cancer. These findings also suggest that drugs that block the effects of cyclin D1 may be useful in blocking the conversion of normal tissue to malignant tissue.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]