Effects of the RXR-specific ligand Targretin on gene expression in carcinogen-induced mammary tumors in the rat
Thomas Hermann, Patricia Tooker, Martin Seidel
& William Lamph
Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, California 92121, USA
Targretin (LGD1069), a high-affinity ligand for the retinoid X receptors (RXRa, RXRb and RXRg), is highly effective in the prevention and treatment of carcinogen-induced breast cancer in various rat models. To understand the molecular basis of the tumor response to Targretin, we used microarray analysis to compare the gene expression profiles of tumors regressing in response to Targretin with those of either vehicle-treated tumors or tumors resisting Targretin treatment. The vehicle-treated and Targretin-resistant tumors had very similar profiles, but the tumors responding to Targretin exhibited broad changes in gene expression. These included genes involved in proliferation, markers of differentiation, tumor markers and expressed sequence tags of unknown function. We selected a subset of these genes for further evaluation. Quantitative analysis by real-time polymerase chain reaction confirmed the differential expression for the majority of the selected genes. However, a small fraction was identified as false positives. We evaluated a subset of the confirmed genes, as well as additional genes with related biological activities, by immunohistochemistry and laser capture microdissection of tumor sections, and their regulation in better-defined in vitro systems is now under investigation.
