The interplay of NR4A receptors and the oncogene–tumor suppressor networks in cancer

Abstract

Nuclear receptor (NR) subfamily 4 group A (NR4A) is a family of three highly homologous orphan nuclear receptors that have multiple physiological and pathological roles, including some in cancer. These NRs are reportedly dysregulated in multiple cancer types, with many studies demonstrating pro-oncogenic roles for NR4A1 (Nur77) and NR4A2 (Nurr1). Additionally, NR4A1 and NR4A3 (Nor-1) are described as tumor suppressors in leukemia. The dysregulation and functions of the NR4A members are due to many factors, including transcriptional regulation, protein-protein interactions, and post-translational modifications. These various levels of intracellular regulation result from the signaling cross-talk of the NR4A members with various signaling pathways, many of which are relevant to cancer and likely explain the family members' functions in oncogenesis and tumor suppression. In this review, we discuss the multiple functions of the NR4A receptors in cancer and summarize a growing body of scientific literature that describes the interconnectedness of the NR4A receptors with various oncogene and tumor suppressor pathways.

The emerging roles of orphan nuclear receptors in prostate cancer

“…NGFI-Bs play dual and opposite roles in the regulation of cell survival and apoptosis via different mechanisms and pathways depending on specific cellular context [79,81]. The pro-apoptotic and anti-apoptotic roles of NGFI-B, as well as the pathways involved in apoptosis triggered by its inactivation, are summarized in the Fig.…”

“…4. Small-molecule agonists or antagonists of NGFI-Bs, which can modulate their transcription functions, can be the potential anti-cancer drugs [79,80]. Methylene-substituted diindolylmethane (DIM) compounds are identified as agonists or antagonists of NGFI-B, and inhibit in vitro and in vivo growth of multiple cancer cells.…”

“…NGFI-B receptors are shown to regulate multiple physiological processes and are involved in diseases, including cancer (recent reviews refer to references [7,[78][79][80].…”

Validation of an oligo-gene signature for the prognostic stratification of ductal carcinoma in situ (DCIS)

“…NR4A1 (on chromosomal band 12q13) is a nuclear orphan hormone receptor. It has pro-apoptotic activity when localized to mitochondria and anti-apoptotic activity when localized to the nucleus [9,10]. This gene was shown to be downregulated in acute myelogenous leukemia, aggressive lymphomas, metastatic melanoma, and follicular thyroid carcinoma [11][12][13][14][15].…”

A Nuclear Attack on Thrombosis and Inflammation

“…Further complicating the picture is the fact that these NR4A members also variably exhibit tumor suppressor or oncogenic properties. 28 In spite of these challenges, the observations of Yang et al 3 are provocative and exciting, as they reveal pathways that have hitherto not been explored in the setting of thrombosis. Teasing out the cell-and stress-specific responses mediated by Nor1 and Nur77 in different thrombosis models, and further clarifying the relevant pathways, will hopefully uncover novel preventative and therapeutic strategies for thrombotic and inflammatory diseases.…”