1. Department of Medicine,
2. Department of Genetics and Development,
3. Department of Urology, and,
4. Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA
5. Center for Advanced Biotechnology and Medicine,
6. Department of Pediatrics, and,
7. Department of Medicine, UMDNJ–Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA
8. Present addresses: Department of Biological Sciences, Sanofi-Aventis, Bridgewater, New Jersey 08807, USA (K.D.E.); Department of Molecular Biology, Bristol-Myers Squibb Research Institute, Princeton, New Jersey 08543, USA (D.W.); Department of Food Science, Rutgers University, Piscataway, New Jersey 08901, USA (H.Y.); Cardiovascular Diseases Group, Merck Research Laboratories, Rahway, New Jersey 07065, USA (M.V.H.); Johnson and Johnson Skin Research Center, Skillman, New Jersey 08558, USA (Y.-P.H.); Department of Medical Oncology, Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA (S.M.P.).

Correspondence to: Michael M. Shen^1,2,5,6 Correspondence and requests for materials should be addressed to M.M.S. (Email: mshen@columbia.edu).

Abstract

In epithelial tissues, the lineage relationship between normal progenitor cells and cell type(s) of origin for cancer has been poorly understood. Here we show that a known regulator of prostate epithelial differentiation, the homeobox gene Nkx3-1, marks a stem cell population that functions during prostate regeneration. Genetic lineage-marking demonstrates that rare luminal cells that express Nkx3-1 in the absence of testicular androgens (castration-resistant Nkx3-1-expressing cells, CARNs) are bipotential and can self-renew in vivo, and single-cell transplantation assays show that CARNs can reconstitute prostate ducts in renal grafts. Functional assays of Nkx3-1 mutant mice in serial prostate regeneration suggest that Nkx3-1 is required for stem cell maintenance. Furthermore, targeted deletion of the Pten tumour suppressor gene in CARNs results in rapid carcinoma formation after androgen-mediated regeneration. These observations indicate that CARNs represent a new luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer.

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