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Model Organisms

Progression of Prostate Cancer from a Subset of p63-Positive Basal Epithelial Cells in FG/Tag Transgenic Mice

¹ Geriatric Research, Education, and Clinical Center and Research Service, Veterans Affairs Medical Center, and ² Department of Medicine and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida

Requests for reprints: Carlos Perez-Stable, Geriatric Research, Education, and Clinical Center (11-GRC), Veterans Affairs Medical Center, 1201 NW 16 Street, Miami, FL 33125. Phone: 305-324-4455, ext. 4391; Fax: 305-575-3365. E-mail: cperez{at}med.miami.edu

Transgenic mice that allow targeting of SV40 T antigen (Tag) to the prostate provide a unique model to identify cancer-initiating cells and follow their progression from a normal cell phenotype into prostate cancer cells. We have developed the FG/Tag transgenic mouse model of prostate cancer using the human fetal globin (FG) promoter linked to Tag. Immunohistochemistry results show that before the development of prostate intraepithelial neoplasia (PIN), a subset of p63⁺ basal epithelial cells expresses Tag. As in the case of human prostate cancer, there is a loss of p63⁺ basal cells with neoplastic progression, and a long period of time is required for PIN lesions to develop into palpable prostate tumors. Other immunohistochemistry results show cellular heterogeneity in FG/Tag PIN lesions and primary tumors with neuroendocrine differentiation. Cell lines derived from primary prostate tumors showed characteristics of a neuroendocrine-epithelial intermediate cell type. The FG promoter has high transcriptional activity in intermediate (DU 145, PC-3) and p63⁺ basal epithelial (LHSR-AR) prostate cancer cells. Therefore, the unexpected development of prostate cancer in the FG/Tag mice may be due to the presence of DNA elements in the FG promoter that can target Tag to specific basal or intermediate cells. We conclude that FG/Tag mouse is a unique model of prostate cancer because the initiating cells are a subset of p63⁺ basal (possibly stem cells), which may be the true cells of origin for carcinogenesis in aggressive human prostate cancer. (Mol Cancer Res 2007;5(11):1171–9)

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