NKX3.1 is a prostate-specific tumor suppressor homeodomain protein encoded by the NKX3.1 homeobox gene in chromosome 8p21. This protein is haploinsufficient and is frequently downregulated during early stages of carcinogenesis in premalignant lesions and prostatic intraepithelial neoplasia. Loss of heterozygosity is present in 60-80% of prostate tumors.

NKX3.1 is expressed in the normal prostatic epithelium, predominantly localized to the nucleus. Primary and metastatic prostatic adenocarcinoma have lower staining intensity compared to the normal prostate. It has been established as a highly sensitive and specific tissue marker of prostatic adenocarcinoma.

In a differential diagnostic setting, NKX3.1 is useful for differentiating prostatic from urothelial carcinoma, sensitivity ranged between 92-94%, along with a 100% specificity. A recent study also demonstrated NKX3.1 utility in identifying metastatic prostatic adenocarcinoma (98% sensitivity, 99% specificity). Combined in a panel with PSA and PSAP, all metastatic prostatic adenocarcinoma were positive for at least one marker.