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PMID: 20935219 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Deficiencies in the Fanconi anemia DNA damage response pathway increase sensitivity to HPV-associated head and neck cancer.

Cancer research ·Vol. 70 ·No. 23 ·2010-12-01 ·Pages 9959-68

Park JW, Pitot HC, Strati K, Spardy N, Duensing S, Grompe M, Lambert PF

Abstract

Patients with the rare genetic disease, Fanconi anemia (FA), are highly susceptible to squamous cell carcinomas arising at multiple anatomic sites including the head and neck region. Human papillomaviruses (HPVs), particularly HPV16, are associated with ∼20% of head and neck squamous cell carcinomas (HNSCCs) in the general population. Some but not other investigators have reported that HNSCCs in FA patients are much more frequently positive for HPV. In addition, studies have demonstrated an interaction between the HPV16 E7 oncoprotein and the FA pathway, a DNA damage response pathway deficient in FA patients. On the basis of these studies, it was hypothesized that the FA pathway contributes to repair of DNA damage induced by HPV16 E7, providing one explanation for why FA patients are predisposed to HPV-associated HNSCCs. To determine the importance of the FA pathway in modulating the oncogenic abilities of E7, we crossed K14E7 transgenic (K14E7) and fancD2 knockout mice (FancD2(-/-)) to establish K14E7/FancD2(-/-) and K14E7/FancD2(+/+) mice and monitored their susceptibility to HNSCC when treated with a chemical carcinogen. K14E7/FancD2(-/-) mice had a significantly higher incidence of HNSCC compared with K14E7/FancD2(+/+) mice. This difference correlated with an increased proliferative index and the increase in expression of biomarkers that are used to assess levels of DNA damage. These animal studies support the hypotheses that FA patients have increased susceptibility to HPV-associated cancer and that the FA DNA damage response pathway normally attenuates the oncogenic potential of HPV16 E7.

MeSH Terms
4-Nitroquinoline-1-oxide Animals Biomarkers, Tumor/genetics,metabolism Carcinoma, Squamous Cell/genetics,metabolism DNA Damage Fanconi Anemia/genetics,metabolism Fanconi Anemia Complementation Group D2 Protein/genetics,metabolism Female Fluorescent Antibody Technique Genetic Predisposition to Disease/genetics Head and Neck Neoplasms/chemically induced,genetics,metabolism Humans Male Mice Mice, 129 Strain Mice, Knockout Mice, Transgenic Papillomavirus E7 Proteins/genetics,metabolism Quinolones Signal Transduction
Chemicals
4-nitroquinolone-1-oxide Biomarkers, Tumor Fancd2 protein, mouse Fanconi Anemia Complementation Group D2 Protein Papillomavirus E7 Proteins Quinolones oncogene protein E7, Human papillomavirus type 16 4-Nitroquinoline-1-oxide
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Park Jung Wook
McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Pitot Henry C
Strati Katerina
Spardy Nicole
Duensing Stefan
Grompe Markus
Lambert Paul F
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-10-1291
Published
2010-12-01
Epub
2010-00-08
Pages
9959-68
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC2999655
Subset
IM
Grants
NCI NIH HHS · R01 CA112598-05 · United States
NCI NIH HHS · R01 CA112598-02 · United States
NCI NIH HHS · CA112598 · United States
NIDCR NIH HHS · R01 DE017315-04 · United States
NIDCR NIH HHS · R01 DE017315-05 · United States
NIDCR NIH HHS · R01 DE017315-01 · United States
NCI NIH HHS · R01 CA112598-04 · United States
NCI NIH HHS · R01 CA112598-03 · United States
NIDCR NIH HHS · R01 DE017315-03 · United States
NCI NIH HHS · R01 CA112598 · United States
NIDCR NIH HHS · DE017315 · United States
NCI NIH HHS · R01 CA112598-01A1 · United States
NIDCR NIH HHS · R01 DE017315-02 · United States
NIDCR NIH HHS · R01 DE017315 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-10-1291 PMC Full Text View journal details
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