Roles for Nkx3.1 in prostate development and cancer

Rajula Bhatia-Gaur, Annemarie A. Donjacour, Peter J. Sciavolino, Minjung Kim, Nishita Desai, Peter Young, Christine R. Norton, Thomas Gridley, Robert Cardiff, Gerald R. Cunha, Cory Abate-Shen, Michael M. Shen

Research output: Contribution to journalArticle

456 Scopus citations

Abstract

In aging men, the prostate gland becomes hyperproliferative and displays a propensity toward carcinoma. Although this hyperproliferative process has been proposed to represent an inappropriate reactivation of an embryonic differentiation program, the regulatory genes responsible for normal prostate development and function are largely undefined. 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. A null mutation for Nkx3.1 obtained by targeted gene disruption results in defects in prostate ductal morphogenesis and secretory protein production. Notably, Nkx3.1 mutant mice display prostatic epithelial hyperplasia and dysplasia that increases in severity with age. This epithelial hyperplasia and dysplasia also occurs in heterozygous mice, indicating haploinsufficiency for this phenotype. 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. The Nkx3.1 mutant mice provide a unique animal model for examining the relationship between normal prostate differentiation and early stages of prostate carcinogenesis.

Original languageEnglish (US)
Pages (from-to)966-977
Number of pages12
JournalGenes and Development
Volume13
Issue number8
DOIs
StatePublished - Apr 15 1999

Keywords

  • Bulbourethral gland
  • Haploinsufficiency
  • Hyperplasia/dysplasia
  • Organogenesis
  • Prostate
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Bhatia-Gaur, R., Donjacour, A. A., Sciavolino, P. J., Kim, M., Desai, N., Young, P., Norton, C. R., Gridley, T., Cardiff, R., Cunha, G. R., Abate-Shen, C., & Shen, M. M. (1999). Roles for Nkx3.1 in prostate development and cancer. Genes and Development, 13(8), 966-977. https://doi.org/10.1101/gad.13.8.966