title: High incidence of female reproductive tract cancers in FA-deficient HPV16-transgenic mice correlates with E7's induction of DNA damage response, an activity mediated by E7's inactivation of pocket proteins.
abstract: Fanconi anemia (FA) is a rare genetic disorder caused by defects in a DNA damage repair system, the FA pathway. FA patients frequently develop squamous cell carcinoma (SCC) at sites that are associated with human papillomavirus (HPV)-driven cancer including the female reproductive tract. To assess experimentally whether FA deficiency increases susceptibility to HPV-associated cervical/vaginal cancer, we monitored cancer incidence in the female lower reproductive tract of FA-deficient mice expressing HPV16 oncogenes, E6 and/or E7. FA deficiency specifically increased the incidence of cancers in mice expressing E7; but this effect was not observed in mice just expressing E6. We also observed that E7, but not E6, induced DNA damage as scored by induction of γ-H2AX and 53BP1 (p53 binding protein 1) nuclear foci, and this induction was heightened in FA-deficient tissue. Finally, we discovered that this induction of DNA damage responses was recapitulated in mice deficient in expression of 'pocket' proteins, pRb, p107 and p130, which are established targets of E7. Our findings support the hypothesis that E7 induces cancer by causing DNA damage at least in part through the inactivation of pocket proteins. This hypothesis explains why a deficiency in DNA damage repair would increase susceptibility to E7-driven cancer.
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: M-K
authors.initials: MK
authors.lastname: Shin
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Lambert
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D049109:Cell Proliferation; D004249:DNA Damage / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000096:biosynthesis; D052162:Human papillomavirus 16 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics*; D050725:Papillomavirus E7 Proteins / Q000096:biosynthesis / Q000235:genetics*; D030361:Papillomavirus Infections / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D002583:Uterine Cervical Neoplasms / Q000235:genetics*
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D051856:Fanconi Anemia Complementation Group Proteins; D006657:Histones; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse; C059731:oncogene protein E7, Human papillomavirus type 16