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 answer #1Cite this page: Thakur S, Enwere E. NKX3.1. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsnkx3.html. Accessed June 7th, 2020.
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
- 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)
- 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)
Essential features
- 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
- NKX3.1 (98.6%) shows better sensitivity than Prostate Specific Antigen (PSA) (94.2%) for identifying metastatic prostatic adenocarcinoma
Terminology
-
Also known as
- NK3 Homeobox 1
- Homeobox Protein NK-3 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 (GeneCards - NKX3.1 Gene)
Pathophysiology
- 3’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
- The 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 prostate intraepithelial lesion (PIN), a precursor of prostate carcinoma (Mol Biol Rep 2010;37:1505)
- Human NKX3.1 gene is located on chromosome 8p21, which is frequently reported to undergo loss of heterozygosity (LOH) during the progression of prostate cancer
- LOH has been reported in 12 - 89% of high grade prostatic intraepithelial neoplasia and 35 - 86% of prostatic adenocarcinomas
- The frequency of LOH on chromosome 8p increases with advancing disease grade (Am J Surg Pathol 2010;34:1097)
- Conditional deletion of one 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 one 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)
- Castration resistant NKX3.1 expressing cells (CARNs) in mice have been found to be bipotential in nature and self renewing
- Single cell transplantation of CARNs reconstitutes prostate ducts in renal grafts; in these mice, NKX3.1 has been shown to be required for stem cell maintenance (Nature 2009;461:495)
- 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)
Interpretation
- Nuclear stain (GeneCards - NKX3.1 Gene)
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, H&E and NKX3.1
Metastatic prostatic adenocarcinoma to bone, H&E
Metastatic prostatic adenocarcinoma to bone, NKX3.1
Contributed by Grzegorz Gurda, M.D., Ph.D., Gundersen Health Systems, Wisconsin
Prostatic adenocarcinoma, Gleason 3+3, 90% staining, 4x, 10x, 20x
Nodular hyperplasia (BPH), 4x, 10x, 20x
Images hosted on other servers:
staining for NKX3.1 in
normal and atrophy
staining for NKX3.1 in
normal and PIN
staining for NKX3.1 in
normal and carcinoma
NKX3.1 staining in normal prostate tissue
with: (A) H&E, (B) NKX3.1, (C)
PSA, (D) PSAP
Positive staining - normal
- Highly expressed in the prostate and at a lower level in the testis (GeneCards - NKX3.1 Gene, 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)
- 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)
Negative staining
- 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
- Prostatic Intraepithelial Neoplasia (PIN)
- Primary prostate adenocarcinoma
- Prostate carcinoma nodal metastasis
Board review answer #1
A. Bladder adenocarcinoma. NKX3.1 staining is typically limited to prostate (benign and malignant) and some breast carcinomas.
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