Stains
NKX3-1

Authors: Satbir Thakur, Ph.D. (see Authors page)
Editor: Emeka Enwere, M.D.
Editorial Board Member Review: Lauren N. Stuart, M.D., M.B.A.

Revised: 24 April 2017, last major update April 2017

Copyright: (c) 2003-2017, PathologyOutlines.com, Inc.

PubMed Search: NKX3-1
Cite this page: NKX3-1. PathologyOutlines.com website. http://pathologyoutlines.com/topic/stainsnkx3.html. Accessed April 25th, 2017.
Definition / General
  • NKX3-1 is a homeodomain containing transcription factor protein that is expressed specifically in prostate gland
  • Its expression is regulated in an androgen specific manner
  • Loss of NKX3-1 protein 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
  • NKX3-1 is a transcription factor that binds to a consensus sequence 5’-TAAGT[AG]-3’
  • It can act as a transcriptional activator or repressor, depending on the tissue and cellular context
  • This protein plays an important role in normal prostate development, regulating proliferation of glandular epithelium and in the formation of ducts in prostate
  • Loss of NKX3-1 is an initiating event in the formation of prostate intraepithelial lesions (PINs), which are precursors 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 loss of heterozygosity on chromosome 8p increases with advancing disease grade (Am J Surg Pathol 2010;34:1097)
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)
Sites
Pathophysiology
  • Conditional deletion of one or both alleles of NKX3-1 in transgenic mice led to the development of preinvasive lesions that resembled human prostatic intraepithelial neoplasia (Mol Cell Biol 2002;22:1495)
  • Targeted disruption of NKX3-1 in mice resulted 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 resulted in aggressive prostate tumorigenesis (Cancer Res 2003;63:3886, Am J Pathol 2004;164:1607)
  • Loss of function of NKX3-1 in mouse prostate resulted in downregulation of genes essential for prostate differentiation (Science 2016;352:1576)
  • Castration resistant NKX3-1-expressing cells (CARNs) in mice were found to be bipotential in nature and self renewing
  • Single cell transplantation of CARNs reconstituted prostate ducts in renal grafts; in these mice, NKX3-1 was shown to be required for stem cell maintenance (Nature 2009;461:495)
  • In humans, loss of NKX3-1 expression was 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 was 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 was shown to increase p53 stability and activity in an MDM2 dependent manner by its association with HDAC1 (Cancer Cell 2006;9:367)
  • NKX3-1 (98.6%) showed better sensitivity for identifying metastatic prostatic adenocarcinomas as compared to clinically used Prostate Specific Antigen (PSA) (94.2%) (Am J Surg Pathol 2010;34:1097)
Micro Description
Micro Images

Images hosted on other servers:

Immunohistochemical
staining for NKX3-1 in
normal and atrophy

Immunohistochemical
staining for NKX3-1 in
normal and PIN

Immunohistochemical
staining for NKX3-1 in
normal and carcinoma

NKX3-1 staining in normal prostate tissue

Soft tissue metastasis stained
with: (A) H&E, (B) NKX3-1, (C)
PSA, (D) PSAP
Positive Stains
Negative Stains
Board Review Questions
    Which of the following would be expected to exhibit the weakest staining for Nkx3-1?

  1. Normal prostatic epithelium
  2. Prostatic Intraepithelial Neoplasia (PIN)
  3. Primary prostate adenocarcinoma
  4. Prostate carcinoma nodal metastasis
Board Review Answers
D. Nkx3-1 expression is gradually lost with progression of prostate adenocarcinoma, at least in part due to loss of heterozygosity at the gene’s locus.