Disease relevance of Nkx3-1

• Emergence of androgen independence at early stages of prostate cancer progression in nkx3.1; pten mice [1].
• We now find that the prostate epithelial cells from these Nkx3.1; Pten mutant mice are capable of surviving and proliferating in the absence of androgens and that they develop androgen-independent phenotypes well before they display overt prostatic intraepithelial neoplasia or cancer phenotypes [1].
• In this report, we have examined the efficacy of 1alpha,25-dihydroxyvitamin D(3) (1,25 D(3)) as a chemopreventive agent using Nkx3.1; Pten mutant mice, which recapitulate stages of prostate carcinogenesis from prostate intraepithelial neoplasia (PIN) to adenocarcinoma [2].
• Notably, Nkx3.1 mutant mice display prostatic epithelial hyperplasia and dysplasia that increases in severity with age [3].
• Loss of NKX3.1 protein expression is common in human prostate carcinomas and prostatic intraepithelial neoplasia (PIN) lesions and correlates with tumor progression [4].

High impact information on Nkx3-1

• Because human NKX3.1 is known to map to a prostate cancer hot spot, we propose that NKX3.1 is a prostate-specific tumor suppressor gene and that loss of a single allele may predispose to prostate carcinogenesis [3].
• Here we show that the murine Nkx3.1 homeobox gene is the earliest known marker of prostate epithelium during embryogenesis and is subsequently expressed at all stages of prostate differentiation in vivo as well as in tissue recombinants [3].
• A null mutation for Nkx3.1 obtained by targeted gene disruption results in defects in prostate ductal morphogenesis and secretory protein production [3].
• Our findings underscore the significance of interactions between tissue-specific regulators such as Nkx3.1 and broad-spectrum tumor suppressors such as Pten in contributing to the distinct phenotypes of different cancers [5].
• In this work, we elucidate how BMP signaling modulates the transcriptional repressor activity of Nkx3 [6].

Chemical compound and disease context of Nkx3-1

• Here we demonstrate that Nkx3.1 allelic loss extends the proliferative stage of regenerating luminal cells, leading to epithelial hyperplasia [7].

Biological context of Nkx3-1

• Homozygous mutant mice for Nkx3.1 were viable and fertile, and the phenotype was, unexpectedly, confined to the prostate and palatine glands [8].
• A murine homolog of bagpipe, Bax/Nkx3.1, is expressed in somites, blood vessels, and the male reproductive system during embryogenesis (this study), suggesting that this gene's function may be relevant for the development of these organs [9].
• Interestingly, Nkx3.1 mapped to the central region of the mouse chromosome 14 and was linked to Nkx2.6, a murine homolog of Drosophila tinman [8].
• Here, we investigated the role of the axial structures in the mediolateral patterning of the somite by using a newly identified murine homeobox gene, Nkx-3.1, as a medial somitic marker in explant in vitro assays [10].
• Targeted disruption of the Nkx3.1 gene in mice results in morphogenetic defects of minor salivary glands: parallels to glandular duct morphogenesis in prostate [11].

Anatomical context of Nkx3-1

• Nkx3.1 is an early marker of the sclerotome and a subset of vascular smooth muscle cells, and at later stages, this gene is expressed in the prostate, palatine glands, kidney, and restricted regions of the central nervous system [8].
• Our results suggest that Nkx3.1 plays a unique role in regulating proliferation of glandular epithelium and in the formation of ducts in prostate and minor salivary glands [11].
• Shh could induce and maintain Nkx-3.1 expression in pre-somitic mesoderm and young somites but not in more mature, differentiated ones [10].
• The genetic locus of Nkx3.1, an early murine marker of sclerotome and prostate development, was disrupted by a knock in of CRE recombinase via homologous recombination in embryonic stem cells [12].
• We found that the expression of Nkx-3.1 in pre-somitic tissue explants is induced by the notochord and maintained in newly-differentiated somites by the notochord and both ventral and dorsal parts of the neural tube [10].

Associations of Nkx3-1 with chemical compounds

• Finally, we observe androgen independence of high-grade PIN lesions after androgen ablation of Nkx3.1(+/-); Pten(+/-) mice [13].
• NKX3.1 binding to Topo I occurred independently of the Topo I NH2-terminal domain [14].

Regulatory relationships of Nkx3-1

• The homeodomain-containing transcription factor NKX3.1 is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner [4].
• In situ hybridization analysis of mid- and late-gestation male embryos shows that Nkx3.1 is expressed in the developing urogenital sinus, testis, and prostatic buds [15].

Other interactions of Nkx3-1

• Transcription factors Nkx3.1 and Nkx3.2 (Bapx1) play an overlapping role in sclerotomal development of the mouse [16].
• Mediolateral patterning of somites: multiple axial signals, including Sonic hedgehog, regulate Nkx-3.1 expression [10].
• We have generated mice carrying compound mutant alleles of Nkx3.1 and p27 to explore the roles of these factors in prostate tumorigenesis [17].
• The homeodomain transcription factor Nkx3.1 and the cyclin-dependent kinase inhibitor p27kip1 have both been implicated in prostate tumor suppression [17].
• Here, we have investigated the malignant potential of the high-grade PIN lesions that form in Nkx3.1(+/-); Pten(+/-) compound mutant mice and demonstrate their neoplastic progression in a serial transplantation/tissue recombination assay [13].

Analytical, diagnostic and therapeutic context of Nkx3-1

• In particular, we have been studying the evolution of androgen independence in Nkx3.1; Pten mutant mice, which develop prostatic intraepithelial neoplasia and adenocarcinoma as a consequence of aging, as well as androgen-independent phenotypes following castration [1].
• CONCLUSION: Our findings show the value of chemoprevention studies using Nkx3.1; Pten mutant mice, particularly for evaluating the efficacy and underlying mechanisms of potential agents and to gain insights about the optimal timing of their delivery [2].
• The Nkx3.1 mutant mice provide a unique animal model for examining the relationship between normal prostate differentiation and early stages of prostate carcinogenesis [3].
• Using a tissue recombination approach, we found that PIN-like lesions from Nkx3.1 mutants can undergo progressively severe histopathological alterations after serial transplantation in nude mice [18].
• Consistent with such a role, here we show that Nkx3.1 displays growth-suppressing activities in cell culture, and that aged Nkx3.1 mutant mice display histopathological defects resembling prostatic intraepithelial neoplasia (PIN), the presumed precursor of human prostate cancer [18].

References