Nuclear receptors are protein molecules found within cells that mediate the activity of hormones and other substances such as certain vitamins. The receptors are all transcription factors, meaning that they possess the ability to bind to DNA and activate genes. Nuclear receptors become active when they detect a certain ligand in the cellular environment.
The ligands that trigger nuclear receptor activity are a diverse group that plays a key role in regulation of both normal physiological processes and tumor development. They include the steroid hormones, including the sex hormones responsible for controlling sexual and reproductive development, and glucocortisoids, which regulate responses to stress. Thyroid hormones are also a member of this group, as are vitamins A and D and their derivatives.
The first evidence for a steroid hormone receptor was reported nearly 50 years ago. During the late 1960s and 1970s, data emerged that the estrogen receptor had a function in the nucleus and evidence began to accumulate supporting a link between steroid receptor activity and gene transcription. In the mid-1980s, the first receptors, for glucocortisoids and thyroid hormones, were cloned. In the past 20 years, the field has exploded as close to 50 receptors have been isolated, their functions explored and their target sequences on DNA, co-activator proteins and co-repressors identified.
Because nuclear receptors share a common physical structure and mechanism of action, they have provided a common ground for understanding a diverse group of physiological and medical phenomena.
Nuclear receptors have been implicated in a wide variety of cancers. Androgen receptors have been implicated in the initiation and progression of prostate cancer. Bone cancer has been linked to the nor-1 receptor, and colon cancer to PPARgamma.
Many breast cancers are due in part to excess levels of activity of estrogen receptors. These tumors, which are termed hormone responsive, can be treated with drugs that act as anti-estrogens by competing with endogenous estrogen for access to receptors. This class of compounds, called selective estrogen receptor modulators (SERMS), binds estrogen receptors in the breast without activating transcription. The occupied receptors are, therefore, unavailable for stimulation by endogenous estrogen.
Estrogen receptor activity can also be suppressed through interaction with nuclear receptors T2 and T4. Because the normal ligands for these receptors are unknown, they are referred to as orphan receptors. Both these receptors are also present in the prostate, where they have been shown to repress the androgen receptor and its activation of prostate specific antigen. These results suggest that either of these receptors might provide points for therapeutic intervention in breast or prostate cancer.
The nuclear receptors RORg, nur77 and nor-1 have also been implicated in a wide variety of leukemias. One form of acute promyelocytic leukemia is caused by a chromosomal rearrangement, a translocation that exchanges parts of chromosomes 15 and 17, resulting in a fusion protein between RAR-alpha and PML, a protein that normally functions as a transcription factor. Therapy with retinoic acid has been demonstrated to induce differentiation, growth arrest and apoptosis of leukemia cells and is an effective therapy for many patients.