Aberrant Expression of Retinoid Receptors and Lung Carcinogenesis
Authors: R. Lotan
Journal: JNCI Journal of the National Cancer Institute (1999)

Lung cancer continues to be the leading cause of cancer deaths in the United States for both women and men (1). The alarmingly low 5-year relative survival rate (<14%) for all patients, regardless of stage at diagnosis, is a grim indication of the shortcomings of the current therapeutic approaches. Therefore, new strategies for preventing and treating lung cancer are urgently needed. One promising approach is chemoprevention with natural and synthetic vitamin A analogues known as retinoids (2,3). The rationale for using retinoids for lung cancer prevention is based on their ability to regulate the growth and differentiation of aerodigestive tract epithelial cells (2) and to prevent lung carcinogenesis in animal models (4). Furthermore, clinical trials have demonstrated the efficacy of retinoids in suppressing oral high-risk noncancerous lesions and reducing second primary cancers in patients with prior head and neck or lung cancer (5). Retinoids exert most of their effects on cell growth and differentiation by regulating gene expression. This regulation is mediated by nuclear retinoid receptors that are members of the steroid receptor gene superfamily. Retinoid receptors function as ligand-dependent transcription-enhancing factors (6). Two subtypes of retinoid receptors have been identified—retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Each of these includes three isotypes designated a, b , and g. RAR genes have been localized to chromosomes 17q21, 3p24, and 12q13, for isotypes a, b, and g, respectively; in contrast, RXR genes have been localized to chromosomes 9q34.3, 6p21.3, and 1q22–23, for isotypes a, b, and g, respectively (6). Each RAR and RXR subtype can be expressed in several isoforms, which differ in their amino terminal domain (6). RARs can form heterodimers with RXRs and recognize retinoic acid response elements that consist of direct repeats (DR) PuG(G/T)TCA(X)nPuG(G/T)TCA with one or five intervening nucleotides (X) or closely degenerate motifs (6). It is interesting that RAR genes themselves contain a DR5 retinoic acid response element in their promoter regions; consequently, their expression can be regulated by all-trans-retinoic acid. RARb2 appears to be tightly regulated by all-trans-retinoic acid (7). RXRs can also form homodimers and activate DR1 retinoid X response element or form heterodimers with other members of the steroid receptor family, thus providing opportunities for cross-talk among different signaling pathways (6). It is thought that each receptor isotype and isoform regulates a distinct subset of retinoid-responsive genes because deletion of individual receptors by homologous recombination resulted in loss of induction by all-trans-retinoic acid of different genes (6). Genetic studies in mice by knockout of individual or multiple receptors have demonstrated both specific and redundant functions of individual RARs (8). Transcriptional regulation by retinoid receptors requires cofactors of two types: corepressors and coactivators. The complexes formed by nuclear retinoid receptors and response element are recognized by corepressors. Ligand binding can alter the conformation of the receptors such that the corepressors dissociate and the coactivators associate with the nuclear retinoid receptors and activate the transcriptional machinery (6,9). The complex retinoid-signaling pathway may be modulated by multiple mechanisms, including changes in the uptake and metabolism of physiologic retinoids by target cells and changes in the expression or function of specific nuclear receptors, cofactors, or corepressors. Because vitamin A deficiency has been associated with enhanced lung carcinogenesis (2,5), it is plausible to suggest that defects in retinoid signaling in a vitamin A-sufficient individual may mimic vitamin A deficiency at the cell level and facilitate malignant transformation and progression. In this issue of the Journal, Picard et al. (10) present the first detailed analysis of the expression of RARs a, b, and g and RXRs a and b at the protein level in normal lung tissue and in non-small-cell lung cancer (NSCLC). The main findings of this investigation are as follows: (a) All of the five receptors were detected by immunohistochemistry in control tissues, which included lung cells from patients without lung cancer and normalappearing lung tissue either distal or adjacent to the lung tumors; (b) stromal cells exhibited a receptor expression pattern similar to that of the lung epithelial cells; and (c) the expression of several types of receptor was altered in NSCLC cells compared with control cells. Several patterns of change in receptor expression were noted: Increased expression in carcinoma relative to control cell nuclei was observed for RARa and RXRa in 26% and 85% of the cases, respectively; in contrast, the rest of the cases expressed comparable levels of these receptors in carcinoma and in controls. The level of RXRb increased moderately in 82% and decreased in 18% of the cases in carcinomas compared with controls. RARg was detected in all of the tumor specimens, but its levels were decreased moderately in some of the carcinomas relative to control cells. Other investigators (11) have observed increased levels of RARa that were associated with higher proliferation in breast cancer relative to normal breast epithelial cells. Increased messenger RNA (mRNA) of RXR was found in ductal intraepithelial neoplasia relative to normal ductal/lobular cells (12). These authors suggested that the increased expression may be involved causally in breast carcinogenesis. It is not known whether the increase in RARa and RXRb proteins in lung cancer is associated with cancer development.