Role of nuclear receptors in lung tumourigenesis.

Nuclear receptors are a family of ligand dependent transcription factors which have important roles in control of growth and differentiation in many cell types. This review will focus on the role of two members of this family (estrogen receptors and PPARgamma) in the initiation and progression of lung cancer. These receptors have been studied in other types of cancer, and the differences between findings in lung cancer and other malignancies will be discussed. We will also describe recent studies on the basic mechanisms of action of these receptors and suggest novel therapeutic targets. Specifically, there is emerging evidence that these receptors can induce gene expression through both ligand-dependent and ligand-independent pathways, and distinct families of genes are likely to be regulated depending on the mechanism of nuclear receptor signalling. These data suggest that a greater understanding of the basic biology and mechanisms of these receptors is required to develop specific pharmacological agents as therapeutics for cancer. Specifically, the development of selective agonists for these receptors, such as tamoxifen, may lead to more selective engagement of anti-tumourigenic pathways. In addition, combinatorial therapy using selective nuclear receptor activators in conjunction with the recently developed EGF receptor inhibitors (gefitinib, erlotinib) may sensitise cells which are unresponsive to the effects of EGF receptor inhibitors alone, providing powerful new therapeutic strategies.