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Clinical Cancer Research Vol. 10, 8521-8530, December 15, 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Transcription Factor AP-2{gamma} Is a Developmentally Regulated Marker of Testicular Carcinoma In situ and Germ Cell Tumors

Christina E. Hoei-Hansen1, John E. Nielsen1, Kristian Almstrup1, Si Brask Sonne1, Niels Graem2, Niels E. Skakkebaek1, Henrik Leffers1 and Ewa Rajpert-De Meyts1

University Departments of 1 Growth and Reproduction, and 2 Pathology, Rigshospitalet, Denmark

Purpose: Transcription factor activator protein-2{gamma} (TFAP2C, AP-2{gamma}) was reported previously in extraembryonic ectoderm and breast carcinomas but not in the testis. In our recent gene expression study we detected AP-2{gamma} in carcinoma in situ testis (CIS, or intratubular germ cell neoplasia), precursor of testicular germ cell tumors. In this study we aimed to investigate the expression pattern of AP-2{gamma} and to shed light on this factor in germ cell differentiation and the pathogenesis of germ cell neoplasia.

Experimental Design: We analyzed expression pattern of AP-2{gamma} at the RNA and protein level in normal human tissues and a panel of tumors and tumor-derived cell lines. In the gonads, we established the ontogeny of expression of AP-2{gamma} in normal and dysgenetic samples. We also investigated the regulation of AP-2{gamma} by steroids and retinoic acid.

Results: We detected abundant AP-2{gamma} in testicular CIS and in testicular germ cell tumors of young adults and confirmed differential expression of AP-2{gamma} in somatic tumors. We found that AP-2{gamma} expression was regulated by retinoic acid in an embryonal carcinoma cell line (NT2). The investigation of ontogeny of AP-2{gamma} protein expression in fetal gonads revealed that it was confined to oogonia/gonocytes and was down-regulated with germ cell differentiation. In some prepubertal intersex cases, AP-2{gamma} was detected outside of the normal window of expression, probably marking neoplastic transformation of germ cells.

Conclusions: AP-2{gamma} is developmentally regulated and associated with the undifferentiated phenotype in germ cells. This transcription factor may be involved in self-renewal and survival of immature germ cells and tissue-specific stem cells. AP-2{gamma} is a novel marker of testicular CIS and CIS-derived tumors.




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