RESUMEN
Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR), has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y)-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5) expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways.
Asunto(s)
Orquiectomía , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/cirugía , Receptores Androgénicos/metabolismo , Proteínas Represoras/genética , Factores de Transcripción SOXB1/genética , Antagonistas de Andrógenos/farmacología , Animales , Benzamidas , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Células Madre Embrionarias/efectos de los fármacos , Células Madre Embrionarias/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Nitrilos , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción SOXB1/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
PURPOSE: The aberrant activity of developmental pathways in prostate cancer may provide significant insight into predicting tumor initiation and progression, as well as identifying novel therapeutic targets. To this end, despite shared androgen-dependence and functional similarities to the prostate gland, seminal vesicle cancer is exceptionally rare. EXPERIMENTAL DESIGN: We conducted genomic pathway analyses comparing patient-matched normal prostate and seminal vesicle epithelial cells to identify novel pathways for tumor initiation and progression. Derived gene expression profiles were grouped into cancer biomodules using a protein-protein network algorithm to analyze their relationship to known oncogenes. Each resultant biomodule was assayed for its prognostic ability against publically available prostate cancer patient gene array datasets. RESULTS: Analyses show that the embryonic developmental biomodule containing four homeobox gene family members (Meis1, Meis2, Pbx1, and HoxA9) detects a survival difference in a set of watchful-waiting patients (n = 172, P = 0.05), identify men who are more likely to recur biochemically postprostatectomy (n = 78, P = 0.02), correlate with Gleason score (r = 0.98, P = 0.02), and distinguish between normal prostate, primary tumor, and metastatic disease. In contrast to other cancer types, Meis1, Meis2, and Pbx1 expression is decreased in poor-prognosis tumors, implying that they function as tumor suppressor genes for prostate cancer. Immunohistochemical staining documents nuclear basal-epithelial and stromal Meis2 staining, with loss of Meis2 expression in prostate tumors. CONCLUSION: These data implicate deregulation of the Hox protein cofactors Meis1, Meis2, and Pbx1 as serving a critical function to suppress prostate cancer initiation and progression.