TY - JOUR

T1 - Transcription factor AP-2gamma is a developmentally regulated marker of testicular carcinoma in situ and germ cell tumors

AU - Hoei-Hansen, Christina E

AU - Nielsen, John E

AU - Almstrup, Kristian

AU - Sonne, Si Brask

AU - Graem, Niels

AU - Skakkebaek, Niels E

AU - Leffers, Henrik

AU - Rajpert-De Meyts, Ewa

N1 - Keywords: Adolescent; Adult; Carcinoma in Situ; Cell Differentiation; Child; Child, Preschool; DNA-Binding Proteins; Female; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Germinoma; Gonadal Dysgenesis; Humans; Infant; Infant, Newborn; Male; Middle Aged; Ovarian Neoplasms; Pregnancy; Steroids; Testicular Neoplasms; Transcription Factor AP-2; Transcription Factors; Tretinoin; Tumor Markers, Biological

PY - 2004

Y1 - 2004

N2 - PURPOSE: Transcription factor activator protein-2gamma (TFAP2C, AP-2gamma) was reported previously in extraembryonic ectoderm and breast carcinomas but not in the testis. In our recent gene expression study we detected AP-2gamma 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-2gamma 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-2gamma 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-2gamma in normal and dysgenetic samples. We also investigated the regulation of AP-2gamma by steroids and retinoic acid. RESULTS: We detected abundant AP-2gamma in testicular CIS and in testicular germ cell tumors of young adults and confirmed differential expression of AP-2gamma in somatic tumors. We found that AP-2gamma expression was regulated by retinoic acid in an embryonal carcinoma cell line (NT2). The investigation of ontogeny of AP-2gamma 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-2gamma was detected outside of the normal window of expression, probably marking neoplastic transformation of germ cells. CONCLUSIONS: AP-2gamma 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-2gamma is a novel marker of testicular CIS and CIS-derived tumors.

AB - PURPOSE: Transcription factor activator protein-2gamma (TFAP2C, AP-2gamma) was reported previously in extraembryonic ectoderm and breast carcinomas but not in the testis. In our recent gene expression study we detected AP-2gamma 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-2gamma 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-2gamma 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-2gamma in normal and dysgenetic samples. We also investigated the regulation of AP-2gamma by steroids and retinoic acid. RESULTS: We detected abundant AP-2gamma in testicular CIS and in testicular germ cell tumors of young adults and confirmed differential expression of AP-2gamma in somatic tumors. We found that AP-2gamma expression was regulated by retinoic acid in an embryonal carcinoma cell line (NT2). The investigation of ontogeny of AP-2gamma 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-2gamma was detected outside of the normal window of expression, probably marking neoplastic transformation of germ cells. CONCLUSIONS: AP-2gamma 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-2gamma is a novel marker of testicular CIS and CIS-derived tumors.

U2 - 10.1158/1078-0432.CCR-04-1285

DO - 10.1158/1078-0432.CCR-04-1285

M3 - Journal article

C2 - 15623634

VL - 10

SP - 8521

EP - 8530

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 24

ER -