Home > Stains & CD markers > NR4A3
Stains & CD markers
NR4A3

Sapna Balgobind, M.B.B.Ch.

Last author update: 22 June 2023
Last staff update: 22 June 2023

Copyright: 2021-2024, PathologyOutlines.com, Inc.

PubMed Search: NR4A3

Sapna Balgobind, M.B.B.Ch.
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Clinical features | Interpretation | Uses by pathologists | Microscopic (histologic) description | Microscopic (histologic) images | Positive staining - disease | Negative staining | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Balgobind S, Cheung V. NR4A3. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsnr4a3.html. Accessed December 22nd, 2024.
Definition / general
  • Protein coding gene involved in various physiological processes, including cell proliferation, differentiation and metabolism (Nat Commun 2019;10:368)
  • Highly sensitive immunohistochemical marker for detecting acinic cell carcinoma of salivary gland (Head Neck Pathol 2021;15:425)
Essential features
  • Enhancer hijacking leads to upregulation of NR4A3, which is the oncogenic driver event in acinic cell carcinoma of the salivary gland
  • NR4A3 positive immunohistochemistry is a sensitive and specific finding in acinic cell carcinoma of the salivary gland (J Oral Maxillofac Res 2021;12:e4)
  • Recurrent translocations of NR4A3 and EWSR1 result in a fusion gene, which is the defining feature of extraskeletal myxoid chondrosarcoma of soft tissue (Nat Commun 2019;10:368)
Terminology
  • NOR1 (neuron derived orphan receptor 1)
Pathophysiology
  • Nuclear receptor subfamily 4, group A (NR4A) proteins are transcription factors that directly modulate gene expression or combine with other factors to repress transmission (Nat Commun 2019;10:368)
  • NR4A subfamily comprises 3 members: nerve growth factor induced gene B (NGFI B / Nur77 or NR4A1), nuclear receptor related protein 1 (Nurr1 or NR4A2) and neuron derived orphan receptor 1 (NOR1 or NR4A3) (Int J Mol Sci 2021;22:11371)
  • They are considered orphan receptors as no known ligand has been identified; instead, they appear to be regulated by other mechanisms, such as posttranslational modification and protein - protein interactions (Biochim Biophys Acta 2014;1843:2543)
  • NR4A3 plays a role in T cell development through regulating apoptosis (EMBO J 1997;16:1865)
  • Expression of NR4A3 in vascular endothelial and smooth muscle cells as well as macrophages and other inflammatory cells appear to play a role in cardiovascular remodeling (Int J Mol Sci 2021;22:11371, Cardiovasc Res 2005;65:609)
Clinical features
  • Acinic cell carcinomas harbor recurrent and specific rearrangements [t(4;9)(q13;q31)] that bring active enhancer regions from the secretory calcium binding phosphoproteins (SCPP) gene cluster in close proximity to the transcription start site (TSS) of transcription factor NR4A3 at 9q31 (Nat Commun 2019;10:368)
  • This leads to upregulation of the NR4A3 gene
  • This process is known as enhancer hijacking: a chromosomal rearrangement results in the translocation of an active enhancer that alters the expression of a gene that is not their original target (Trends Mol Med 2021;27:1060)
  • NR4A3 immunohistochemistry has been found to be a sensitive marker for salivary gland acinic cell carcinoma (J Oral Maxillofac Res 2021;12:e4)
  • The defining oncogenic driver event in extraskeletal myxoid chondrosarcoma of soft tissue is a recurrent translocation [t(9;22)(q31;q12)] that creates a fusion gene comprised of NR4A3 and EWSR1 (Nat Commun 2019;10:368)
  • However, NR4A3 immunohistochemistry is not sensitive for the diagnosis of extraskeletal myxoid chondrosarcoma and therefore is not clinically useful (Am J Surg Pathol 2019;43:1726)
  • Reason for a lack of NR4A3 positivity in extraskeletal myxoid chondrosarcoma has been proposed
    • It is noted that in extraskeletal myxoid chondrosarcoma, the gene rearrangements lead to the creation of fusion oncogenes and the expression of novel fusion onocoproteins, rather than upregulation of the NR4A3 gene through enhancer hijacking
    • Epitope identified by the H7 mouse monoclonal antibody used in the study may be expressed differently in extraskeletal myxoid chondrosarcoma associated fusion oncoproteins, hence the lack of staining in extraskeletal myxoid chondrosarcoma (Am J Surg Pathol 2019;43:1726)
Interpretation
  • Nuclear staining
Uses by pathologists
Microscopic (histologic) description
  • Strong and diffuse nuclear staining in acinic cell carcinoma of salivary gland
Microscopic (histologic) images

Contributed by Sapna Balgobind, M.B.B.Ch. and Veronica Cheung, M.Ch.D.
Serous acinar differentiation

Serous acinar differentiation

Zymogen granules

Zymogen granules

Poorly differentiated acinic cell carcinoma

Poorly differentiated acinic cell carcinoma

NR4A3 positive nuclear staining

NR4A3 positive nuclear staining

NR4A3 immunohistochemical stain   NR4A3 immunohistochemical stain

NR4A3 immunohistochemical stain

Positive staining - disease
Negative staining
Molecular / cytogenetics description
  • Fluorescent in situ hybridization (FISH)
  • Reverse transcriptase polymerase chain reaction (RT PCR)
    • EWSR1::NR4A3 fusion can be detected by RT PCR in the majority of extraskeletal myxoid chondrosarcoma cases (Hum Pathol 2014;45:1084)
    • Smaller proportion of extraskeletal myxoid chondrosarcoma cases show NR4A3 fused to other gene partners, including TAF15, TCF12 and TFG (Hum Pathol 2014;45:1084)
Molecular / cytogenetics images

Contributed by Sapna Balgobind, M.B.B.Ch. and Veronica Cheung, M.Ch.D.
Rearrangement present

Rearrangement present

Sample pathology report
  • Salivary gland, resection:
    • Acinic cell carcinoma (see comment)
    • Comment: Sections from salivary gland show a tumor composed of cells with serous acinar differentiation and distinct zymogen granules. The tumor cells show diffuse strong positive nuclear staining for NR4A3 on immunohistochemistry.
Board review style question #1


What type of staining would be expected on NR4A3 immunohistochemistry in acinic cell carcinomas?

  1. Cytoplasmic staining
  2. Membranous staining
  3. No staining
  4. Nuclear and cytoplasmic staining
  5. Strong nuclear staining
Board review style answer #1
E. NR4A3 shows strong nuclear staining in acinic cell carcinomas. Answers A - D are incorrect because the other staining patterns listed are not compatible with what is seen in NR4A3 immunohistochemistry.

Comment Here

Reference: NR4A3
Board review style question #2
What is the mechanism by which NR4A3 is upregulated in acinic cell carcinomas in the salivary gland?

  1. Enhancer deletion
  2. Enhancer hijacking
  3. Enhancer methylation
  4. Enhancer misregulation
  5. Enhancer mutation
Board review style answer #2
B. Enhancer hijacking. The chromosomal rearrangement t(4;9)(q13;q31) results in the translocation of the active enhancer, which leads to upregulation of the target gene. Answers A and C - E are incorrect because the other mechanisms of action listed are not the cause of NR4A3 upregulation in acinic cell carcinomas.

Comment Here

Reference: NR4A3
Back to top
Home > Stains & CD markers > NR4A3
Image 01 Image 02