Deficiency of DNA repair nuclease ERCC1-XPF promotes prostate cancer progression in a tissue recombination model.
BACKGROUND
The excision repair cross complementing (ERCC1) gene product plays a vital role in the nucleotide excision repair (NER) and DNA interstrand crosslink repair pathways, which protect the genome from mutations and chromosomal aberrations, respectively. Genetic deletion of Ercc1 in the mouse causes dramatically accelerated aging. We examined the effect of Ercc1 deletion in the development of prostate cancer in a prostate recapitulation model as Ercc1 deficient mice die within four weeks of birth.


METHODS
Prostate tissues from Ercc1(-/-) mice or wild-type littermates were combined with embryonic rat urogenital mesenchyme and grown as renal grafts for a total of 8, 16, and 24 weeks before histological, expression and proliferative evaluation.


RESULTS
Invasive adenocarcinoma was observed in Ercc1(-/-) tissue recombinants but not wild-type as early as 8 weeks post-grafting. PIN-like lesions in Ercc1(-/-) tissue recombinants had more cytologic and architectural atypia than wild-type (P = 0.02, P = 0.0065, and P = 0.0003 at the 8, 16, and 24 weeks, respectively), as well as more proliferative cells (P = 0.022 and P = 0.033 at 8 and 16 weeks, respectively). With serial grafting, Ercc1(-/-) tissue recombinants progressed to a more severe histopathological phenotype more rapidly than wild-type (P = 0.011).


CONCLUSIONS
Results show that ERCC1 and by implication the NER and/or interstrand crosslink repair mechanisms protect against prostate carcinogenesis and mutations or polymorphisms affecting these DNA repair pathways may predispose prostate epithelial cells to transformation.
Department of Urology, University of Pittsburgh, Pittsburgh, PA, USA.
Derek J
DJ
Matoka
Veronica
V
Yao
Diana S
DS
Harya
Jennifer L
JL
Gregg
Andria R
AR
Robinson
Laura J
LJ
Niedernhofer
Anil V
AV
Parwani
Christoph
C
Maier
Dean J
DJ
Bacich
D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D004260:DNA Repair / Q000235:genetics; D049914:DNA Repair-Deficiency Disorders / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004720:Endonucleases / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000235:genetics*
D004268:DNA-Binding Proteins; C095888:xeroderma pigmentosum group F protein; C071447:ERCC1 protein, human; D004720:Endonucleases