Nuclear Receptors,Transcriptional Regulation,and Oncogenesis

The role of steroid hormones in hormonally dependent neoplasia has been well documented (1). In this Minireview, I will discuss the structure and function of members of the steroid/thyroid (nuclear) receptor superfamily, the mechanism by which they regulate gene transcription, and their potential role in oncogenesis. I will not extensively discuss mutant nuclear receptors that have been found to be associated with various tumors (2) or the regulation of protooncogene expression by nuclear receptor/hormone complexes (3), as these subjects have been recently reviewed elsewhere. Rather, I will concentrate on some recent results that have been obtained using molecular approaches with cloned receptor genes. These studies point to some potentially novel and complex mechanisms whereby steroid/thyroid hormones and their receptors may regulate gene expression and carcinogenesis. Some of what is discussed here will be of a speculative nature, and it is hoped that this will point toward future research approaches that will lead to a greater understanding of the roles for these receptors in neoplastic transformation.

Structure of Nuclear Receptors

Nuclear receptor proteins are ligand-dependent transcription factors and include proteins that bind glucocorticoids, estrogens, progestins, androgens, mineralocorticoids, thyroid hormone, vitamin D, and reti-noic acid (4). Two other potential members may bind xenobiotic ligands that have been directly implicated in carcinogenesis (5, 6). In addition, molecular cloning of cDNA from various cells based on DNA sequence homology has identified numerous other potential members of this superfamily, the so-called “orphan receptors” (7; see below). A diagrammatic representation of the structure of the known nuclear receptors is seen in Figure 1. A nonconserved amino terminus of varying length (the modulating domain) is followed by a highly conserved DNA-binding domain. This domain contains two cysteine “zinc fingers,” which are involved in specific binding of the receptor to a DNA sequence called the “response element.”