Stains & CD markers
NKX3.1


Minor changes: 18 June 2021

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PubMed Search: NKX3.1 stain

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Cite 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
  • 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)
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
Positive staining - disease
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
Board review style question #1
Which of the following would be expected to exhibit the weakest staining for NKX3.1?

  1. Bladder adenocarcinoma
  2. Normal prostatic epithelium
  3. Primary prostate adenocarcinoma
  4. Prostate carcinoma nodal metastasis
  5. 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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