Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Interpretation | Uses by pathologists | Microscopic (histologic) images | Positive staining - normal | Positive staining - disease | Negative staining | Additional references | Board review style question #1 | Board review style answer #1Cite this page: Thakur S, Enwere E. NKX3.1. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsnkx3.html. Accessed June 23rd, 2021.
Definition / general
- Homeodomain containing transcription factor protein that is expressed specifically in prostate gland and binds to a consensus sequence
5'-TAAGT[AG]-3' - Expression is regulated in an androgen specific manner
- Human NKX3.1 gene encodes a 234 amino acid protein and is homologous to the Drosophila bagpipe gene, which is essential in mesoderm development (Mol Cell Biol 2002;22:1495, Eur J Cell Biol 2010;89:273)
- Loss of expression is commonly reported in human prostate carcinomas and prostatic intraepithelial neoplasia, due to allelic loss, promoter methylation and posttranscriptional silencing (Differentiation 2008;76:717)
Essential features
- NKX3.1 can generally be used as a diagnostic biomarker for prostate cancer and other metastatic lesions originating in the prostate
- NKX3.1 (98.6%) shows better sensitivity than prostate specific antigen (PSA) (94.2%) for identifying metastatic prostatic adenocarcinoma (Am J Surg Pathol 2010;34:1097)
- The human NKX3.1 gene is located on chromosome 8p21, which undergoes loss of heterozygosity (LOH) during the progression of prostate cancer
Terminology
- Also known as:
- NK3 homeobox 1
- Homeobox protein NK3 homolog A
- NKX3-1
- NKX3A
- NK3 transcription factor related, locus 1 (Drosophila)
- NK3 transcription factor related, locus 1
- NK homeobox (Drosophila), family 3, A
- NK3 transcription factor homolog A
- NK homeobox, family 3, A
- Homeobox protein Nkx-3.1
- BAPX2
- NKX3
- Reference: GeneCards: NKX3-1 Gene [Accessed 24 February 2021]
Pathophysiology
- NKX3.1 is a prostate specific gene encoding a transcription factor that plays an important role in prostate development and carcinogenesis (Mol Biol Rep 2010;37:1505)
- Can act as a transcriptional activator or repressor, depending on the tissue and cellular context
- Plays an important role in normal prostate development, regulating proliferation of glandular epithelium and in the formation of ducts in prostate
- Expression of mammalian NKX3.1 is androgen dependent and is frequently reduced or lost in prostate cancer (Genes Dev 1999;13:966, Genomics 1997;43:69, Cancer Res 2000;60:6111)
- Loss of NKX3.1 is an initiating event in the formation of prostatic intraepithelial lesion (PIN), a precursor of prostate carcinoma (Mol Biol Rep 2010;37:1505)
- The human NKX3.1 gene is located on chromosome 8p21, which is frequently reported to undergo LOH during the progression of prostate cancer
- LOH at 8p is the most common genetic alteration, found in 40% of prostatic adenocarcinomas (Cancer Cell 2010;18:11)
- Frequency of LOH on chromosome 8p increases with advancing disease grade (Am J Surg Pathol 2010;34:1097)
- In humans, loss of NKX3.1 expression has been shown to be strongly associated with hormone refractory disease and metastases in prostate cancer (Cancer Res 2000;60:6111)
- In oral squamous cell carcinoma (OSCC), association between NKX3.1 loss and occult lymph node metastatic lesions has been observed; loss of NKX3.1 emerged as a significant risk factor to decrease the disease free and overall survival of OSCC patients (Int J Oncol 2012;40:1907)
- NKX3.1 has been shown to increase p53 stability and activity in an MDM2 dependent manner by its association with HDAC1 (Cancer Cell 2006;9:367)
- Mice studies:
- Conditional deletion of 1 or both alleles of NKX3.1 in transgenic mice leads to the development of preinvasive lesions that resemble human prostatic intraepithelial neoplasia (Mol Cell Biol 2002;22:1495)
- Targeted disruption of NKX3.1 in mice results in defects in prostate branching morphogenesis, epithelial cell differentiation, growth and protein secretion (Genes Dev 1999;13:966)
- In mice with targeted disruption of PTEN or CDKN1B, loss of 1 or both alleles of NKX3.1 results in aggressive prostate tumorigenesis (Cancer Res 2003;63:3886, Am J Pathol 2004;164:1607)
- Loss of function of NKX3.1 in mouse prostate results in downregulation of genes essential for prostate differentiation (Science 2016;352:1576)
- In mice, a lineage of castration resistant NKX3.1 expressing cells are stem cells capable of initiating prostate cancer (Nature 2009;461:495)
Interpretation
- Nuclear stain (GeneCards: NKX3-1 Gene [Accessed 24 February 2021])
Uses by pathologists
- Due to its highly restricted expression in prostate epithelial cells, NKX3.1 can be used as a diagnostic biomarker for prostate cancer and other metastatic lesions originating in the prostate (Am J Surg Pathol 2014;38:e6, Adv Anat Pathol 2015;22:149)
- NKX3.1 (98.6%) shows better sensitivity than prostate specific antigen (PSA) (94.2%) for identifying metastatic prostatic adenocarcinomas (Am J Surg Pathol 2010;34:1097)
Microscopic (histologic) images
Contributed by Debra Zynger, M.D.
Prostate needle cores with prostatic adenocarcinoma
Metastatic prostatic adenocarcinoma to bone
Contributed by Grzegorz Gurda, M.D., Ph.D.
Prostatic adenocarcinoma, Gleason 3 + 3, 90% staining
Nodular hyperplasia (BPH)
Positive staining - normal
- Highly expressed in the prostate and at a lower level in the testis (GeneCards: NKX3-1 Gene [Accessed 24 February 2021], Prostate 2003;55:111)
- Salivary gland tissue; bronchial submucosal glands; isolated regions of transitional epithelium in the ureter
Positive staining - disease
- Prostatic adenocarcinoma (Prostate 2003;55:111, Am J Surg Pathol 2007;31:1246)
- Adenoid basal cell carcinoma (Pathology 2021;53:193)
- There is some controversy with respect to the expression of NKX3.1 in EWSR1-NFATc2 sarcoma and mesenchymal chondrosarcoma:
- 1 group demonstrated positive expression in both tumor types and supported these findings in a separate study with further staining and RNA expression assays (Am J Surg Pathol 2020;44:719, Am J Surg Pathol 2021 [Epub ahead of print])
- 2 other groups, however, were unable to reproduce these findings (Mod Pathol 2020;33:1930, Histopathology 2021;78:334)
- Use of NKX3.1 staining in characterization of these tumor types should be applied with caution and ideally with excellent immunohistochemical controls
Negative staining
- Usually negative but may be seen in invasive lobular carcinoma (27%), metastatic lobular carcinoma (25%), invasive ductal carcinoma (2 - 9%) and metastatic ductal carcinoma (5%) (J Clin Pathol 2014;67:768, Prostate 2003;55:111)
- All other organs stain negatively for this protein
Additional references
Board review style question #1
Which of the following would be expected to exhibit the weakest staining for NKX3.1?
- Bladder adenocarcinoma
- Normal prostatic epithelium
- Primary prostate adenocarcinoma
- Prostate carcinoma nodal metastasis
- Prostatic intraepithelial neoplasia (PIN)
Board review style answer #1
A. Bladder adenocarcinoma. NKX3.1 staining is typically limited to prostate (benign and malignant) and some breast carcinomas.
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Reference: NKX3.1
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Reference: NKX3.1
