No abstract

In this study, we have analyzed the expression of TRIM24/TIF-1␣, a negative regulator of various transcription factors (including nuclear receptors and p53) at the genomic, mRNA, and protein levels in human breast tumors. In breast cancer biopsy specimens, TRIM24/TIF-1␣ mRNA levels (assessed by Real-Time Quantitative PCR or microarray expression profiling) were increased as compared to normal breast tissues. At the genomic level, array comparative genomic hybridization analysis showed that the TRIM24/TIF-1␣ locus (7q34) exhibited both gains and losses that correlated with mRNA levels. By re-analyzing a series of 238 tumors, high levels of TRIM24/TIF-1␣ mRNA significantly correlated with various markers of poor prognosis (such as the molecular subtype) and were associated with worse overall survival. By using a rabbit polyclonal antibody for immunochemistry, the TRIM24/TIF-1␣ protein was detected in nuclei of normal luminal epithelial breast cells, but not in myoepithelial cells. Tissue microarray analysis confirmed that its expression was increased in epithelial cells from normal to breast infiltrating duct carcinoma and correlated with worse overall survival. Altogether, this work is the first study that shows that overexpression of the TRIM24/TIF-1␣ gene in breast cancer is associated with poor prognosis and worse survival, and it suggests that this transcription coregulator may play a role in mammary carcinogenesis and represent a novel prognostic marker.

Peroxisome proliferator-activated receptor ␥ (PPAR␥) might not be permissive to ligand activation in prostate cancer cells. Association of PPAR␥ with repressing factors or posttranslational modifications in PPAR␥ protein could explain the lack of effect of PPAR␥ ligands in a recent randomized clinical trial. Using cells and prostate cancer xenograft mouse models, we demonstrate in this study that a combination treatment using the PPAR␥ agonist pioglitazone and the histone deacetylase inhibitor valproic acid is more efficient at inhibiting prostate tumor growth than each individual therapy. We show that the combination treatment impairs the bone-invasive potential of prostate cancer cells in mice. In addition, we demonstrate that expression of E-cadherin, a protein involved in the control of cell migration and invasion, is highly up-regulated in the presence of valproic acid and pioglitazone. We show that E-cadherin expression responds only to the combination treatment and not to single PPAR␥ agonists, defining a new class of PPAR␥ target genes. These results open up new therapeutic perspectives in the treatment of prostate cancer.Prostate cancer is the most common form of cancer in men and the second leading cause of cancer deaths. Tumor growth is originally androgen dependent. Androgens exert their effects through activation of the androgen receptor (AR), a member of the hormone nuclear receptor superfamily. In the mature prostatic gland, the AR regulates the expression of genes involved in cell division and proliferation of the epithelial cells (26). The AR is also involved in several other aspects of prostate cellular metabolism, including lipid biosynthesis, and controls the production of specialized secretory proteins with prostate-restricted expression, such as prostate-specific antigen (PSA) (26). When prostate cancer is still hormone dependent, androgen ablation therapy causes regression of the tumor (18), likely through inactivation of the transcription of the AR target genes. However, the durability of this response is inadequate and many men develop recurrent androgen-independent prostate cancer, which has a very poor prognosis (see reference 11 for a review). Other nuclear receptors or locally produced factors that interact with nuclear receptors are likely involved in cell proliferation, differentiation, and apoptosis in the prostate. The peroxisome proliferator-activated receptor ␥ (PPAR␥) is one such factor. PPAR␥ is another member of the hormone nuclear receptor superfamily. As for most of the other members of this family, its activity is regulated by ligands. Prostaglandin J2 and the antidiabetic drugs thiazolidinediones have been determined to be natural and synthetic ligands of PPAR␥, respectively (for a review, see reference 9). PPAR␥ is highly expressed in the adipose tissue and is required for its development through regulation of the expression of adipocyte-specific genes, such as lipoprotein lipase or the fatty acid transport protein aP2. PPAR␥ is expressed in several other tissues in add...