Diethylstilbestrol effects and lymphomagenesis in Mlh1-deficient mice.
Inherited defects in DNA mismatch repair (MMR) predispose to a variety of malignancies in humans and in mouse knockout models. In humans, hemizygosity for one of several DNA MMR genes greatly increases an individual's risk for colon and endometrial carcinoma. Hemizygous mice develop gastrointestinal tumors at a low to moderate frequency. Homozygous nulls have higher rates of gastrointestinal tumors and are particularly susceptible to lymphoma. In an effort to model endometrial carcinoma associated with mutation in MMR, we treated mice carrying knockout alleles for Mlh1 or Msh2 with the synthetic estrogen diethylstilbestrol (DES), a known promoter of uterine endometrial carcinoma. The C57BL/6 mice carrying DNA MMR mutations failed to develop endometrial carcinomas. However, the Mlh1-deficient mice treated with DES tended to become moribund at an early age and had very early onset of lymphoma. Comparison of DES-treated and untreated Mlh1-/- animals suggests the combination of Mlh1 deficiency and DES exposure accelerates lymphomagenesis.
Kabbarah
Omar
O
Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA.
Sotelo
Andrea K
AK
Mallon
Mary Ann
MA
Winkeler
Erin L
EL
Fan
Ming-Yu
MY
Pfeifer
John D
JD
Shibata
Darryl
D
Gutmann
David H
DH
Goodfellow
Paul J
PJ
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins; D004260:DNA Repair; D004054:Diethylstilbestrol / Q000633:toxicity*; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D004054:Diethylstilbestrol; D000070957:MutL Protein Homolog 1