Comparative analysis of cervical cancer in women and in a human papillomavirus-transgenic mouse model: identification of minichromosome maintenance protein 7 as an informative biomarker for human cervical cancer.
Human papillomaviruses (HPVs), such as HPV-16, are associated with >99% of cervical cancers in women. Two viral oncogenes, E6 and E7, are selectively expressed in these cancers. K14E6 and K14E7 transgenic mouse strains, which express the HPV16 E6 or E7 gene in stratified squamous epithelia, display many acute and long-term phenotypes indicative of the oncogenic potential of E6 and E7 including epithelial hyperplasia, abrogation of normal DNA damage responses, and spontaneous skin tumors. When treated with estrogen, these HPV-16 transgenic mice develop a progressive disease leading to cervical cancer that shows many histopathological parallels to cervical cancer in women. In this study, we evaluated the cervical lesions that arise in these transgenic mice for the expression of biomarkers induced in human cervical cancer. These analyses, which showed close parallels in the timing and pattern of expression of cyclin E and Ki-67 in the mouse cervical disease compared with that in humans, provided further validation of this HPV-16 transgenic mouse model for human cervical cancer. We then used our mouse model to identify minichromosome maintenance protein 7 (MCM7), an E2F-induced cellular DNA replication factor, as a novel biomarker for cervical cancer. In both the mouse and human disease, strong, full thickness staining for MCM7 was seen selectively in the epithelium of high-grade intraepithelial lesions and in frank cancer. The uniform staining pattern and strong signal for MCM7 suggest that MCM7 may be a highly informative biomarker for cervical cancer.
Brake
Tiffany
T
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.
Connor
Joseph P
JP
Petereit
Daniel G
DG
Lambert
Paul F
PF
D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D064168:Minichromosome Maintenance Complex Component 7; D009687:Nuclear Proteins / Q000096:biosynthesis*; D009856:Oncogene Proteins, Viral / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology*
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; C101624:MCM7 protein, human; C491086:Mcm7 protein, mouse; D064168:Minichromosome Maintenance Complex Component 7