By Cary J. Buresh, M.D.


In this issue of THE FOCUS, we introduce our latest prostate marker, NKX3.1.  Located on the short arm of chromosome 8 (8p21.2) is NKX3.1, an androgen-regulated homeobox gene, which codes for a transcription factor involved in the development of the  prostate and testis, as well as in the maintenance of normal secretory function of the prostate.

In the prostate, NKX3.1 expression is restricted to secretory and basal epithelial cells and, like other transcription factors, is expressed only in the nuclei of these cells. Stromal cells, endothe-lial cells, and infiltrating lymphocytes are  negative.


Classic oncogenes and tumor suppressor genes have not been found to play a significant role in the pathogenesis of prostate cancer, but compar-ative genomic hybridization (CGH) has shown gains and losses of genetic material at multiple chromosomal sites, and many genes have been implicated in prostate cancer progression. Alt-hough no mutations have been identified in NKX3.1, early work suggested  that decreased expression may be associated with prostate  cancer progression.

However, there have been conflicting reports  regarding the expression of the gene product, NKX3.1, with tumor progression. Some authors found decreased expression in hormone-refractory disease and advanced tumor stage. Other investi-gators have observed NKX3.1 reactivity in all grades of malignant epithelium and in most  metastatic tumors.

In an examination of 19 poorly differentiated prostatic adenocarcinomas (Gleason grade 10) and a tissue microarray of metastatic prostate cancer, Epstein, et al. found that only 8 of 19 tumors (42%) stained with prostate-specific antigen (PSA), 17 of 19 tumors (89%) stained with  prostatic acid phosphatase (PSAP), and 18 of 19  tumors (95%) stained with NKX3.1, with most ases showing strong and diffuse nuclear reac-tivity. Metastatic prostate carcinoma was posi-tive in 52 of 61 cases (85%). For specificity, several non-prostate tumors were also stained.  NKX3.1 was negative in all cases, as was PSA.  However, PSAP did show patchy reactivity in two rectal carcinoids, a known diagnostic pitfall in the diagnosis of prostate cancer.


In a further study of the utility of NKX3.1 in the work-up of metastatic carcinoma of unknown primary site, Gurel, et al. found that the vast  majority of metastatic prostatic adenocarcino-mas (98.6%) retained NKX3.1 expression, while only 1 of 383 cases of nonprostatic tumors  expressed NKX3.1 and that tumor was a lobular carcinoma of the breast.  The utility of NKX3.1 is also reflected in the finding that it is expressed predominantly in the nucleus, increasing diag-nostic confidence when there is only weak  staining for one or more of the more frequently used cytoplasmic markers.

These results indicate that NKX3.1 may be a more sensitive marker of prostatic adenocarcino-ma than PSA and PSAP, even in very high-grade tumors.


In addition to prostate epithelial cells and  prostate cancer, expression of NKX3.1 has also been reported in normal testis, benign salivary glands and bronchial submucosal glands, isolat-ed regions of transitional epithelium in the  ureter, and some cases of ductal and lobular breast carcinoma. In the adult testis, reactivity appears to be limited to Sertoli cells.  Immunostains for prostate-specific antigen (PSA), prostatic acid phosphatase (PSAP), and prostate-specific membrane antigen (PSMA) are still available at PROPATH, and we now offer  immunostains for NKX3.1.



Gurel B, et al.  NKX3.1 as a Marker of Prostatic Origin in Metastatic Tumors.  The American Journal of Surgical Pathology  34(8):1097-1105, 2010.

Ali TZ, Epstein JI, et al.  NKX3.1 as a New Tissue Marker of Prostatic Adenocarcinoma.  Laboratory Investigation  86(Supplement 1):128A (abstract #582), January 2006.

Rubin MA, DeMarzo AM.  Molecular genetics of human prostate can-cer.  Modern Pathology  17(3):380-388, 2004.

Gelmann EP, Bowen C, Bubendorf L.  Expression of NKX3.1 in Nor-mal and Malignant Tissues.  The Prostate  55(2):111-117, May 2003.

Ornstein DK, Cinquanta M, et al.  Expression Studies and Mutational Analysis of the Androgen Regulated Homeobox Gene NKX3.1 in Be-nign and Malignant Prostate Epithelium.  Journal of Urology  165(4):1329-1334, 2001.

Date of last revision: March 2011.