Pan-Cancer Analyses of the Nuclear Receptor Superfamily

Abstract

Nuclear receptors (NR) act as an integrated conduit for environmental and hormonal signals to govern genomic responses, which relate to cell fate decisions. We review how their integrated actions with each other, shared co-factors and other transcription factors are disrupted in cancer. Steroid hormone nuclear receptors are oncogenic drivers in breast and prostate cancer and blockade of signaling is a major therapeutic goal. By contrast to blockade of receptors, in other cancers enhanced receptor function is attractive, as illustrated initially with targeting of retinoic acid receptors in leukemia. In the post-genomic era large consortia, such as The Cancer Genome Atlas, have developed a remarkable volume of genomic data with which to examine multiple aspects of nuclear receptor status in a pan-cancer manner. Therefore to extend the review of NR function we have also undertaken bioinformatics analyses of NR expression in over 3000 tumors, spread across six different tumor types (bladder, breast, colon, head and neck, liver and prostate). Specifically, to ask how the NR expression was distorted (altered expression, mutation and CNV) we have applied bootstrapping approaches to simulate data for comparison, and also compared these NR findings to 12 other transcription factor families. Nuclear receptors were uniquely and uniformly downregulated across all six tumor types, more than predicted by chance. These approaches also revealed that each tumor type had a specific NR expression profile but these were most similar between breast and prostate cancer. Some NRs were down-regulated in at least five tumor types (e.g. NR3C2/MR and NR5A2/LRH-1)) whereas others were uniquely down-regulated in one tumor (e.g. NR1B3/RARG). The downregulation was not driven by copy number variation or mutation and epigenetic mechanisms maybe responsible for the altered nuclear receptor expression.

Role of glucocorticoid signaling in urothelial tumorigenesis: Inhibition by prednisone presumably through inducing glucocorticoid receptor transrepression

“…Meanwhile, some glucocorticoids, including PRED, are known to have weak mineralocorticoid activity, whereas others, especially synthetic glucocorticoids such as DEX, betamethasone, and triamcinolone showing insignificant inhibitory effects in the present study, have no such potency . These findings, together with other data demonstrating a significantly lower risk of developing bladder cancer in hypertensive patients treated with a mineralocorticoid receptor (MR) antagonist spironolactone as well as downregulation of MR expression in bladder cancer samples, may indicate the involvement of glucocorticoid‐mediated MR signaling in urothelial tumorigenesis. It is still of importance to determine why most of the glucocorticoids have little or no impact on urothelial tumorigenesis.…”

Vitamin D Receptor Signaling and Cancer

“…[296][297][298][299][300] Bootstrapping approaches 301 established that, across cancers, only the NR family was significantly downregulated, but was neither significantly mutated nor altered by copy number variation. 302 Within the NRs, we found that several NRs were uniquely suppressed in only one tumor site, including VDR in the colon cancer (COAD) cohort; this finding may reflect the strong expression of VDR in the normal colon. VDR downregulation was not found to be driven by copy number variation or mutation and thus epigenetic mechanisms may be primarily responsible for altered expression.…”

The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer

“…These data are publically available and were downloaded. The data actually include tumors and normal samples and, therefore, we created an expression table of all genes detectable in at least 80% of tumors ( n = 16,785) given as relative Z -scores as compared to the mean of the normal [150]. Expression of the 165 gene-panel of the DNA methylation pathway was examined in this table using to capture only those genes altered by more than two Z -scores in 25% of tumors; this yielded 21 genes on the DNA methylation pathway.…”