Absence of full-length Brca1 sensitizes mice to oxidative stress and carcinogen-induced tumorigenesis in the esophagus and forestomach.
Environmental and genetic factors are important both in affecting life span and neoplastic transformation. We have shown previously that mice, which are homozygous for full-length breast cancer-associated gene-1 (Brca1) deletion and heterozygous for a p53-null mutation (Brca1(Delta11/Delta11)p53(+/-)), display premature aging and high frequency of spontaneous lymphoma and mammary tumor formation. To investigate the role of Brca1 in regulation of organ homeostasis and susceptibility of Brca1 deficiency to environmental carcinogens, we examined biological function of Brca1 in maintaining organ homeostasis and carcinogen-induced tumorigenesis. Brca1(Delta11/Delta11)p53(+/-) mice showed altered gastrointestinal tract homeostasis, including hyperkeratosis in the esophagus and forestomach. At 6 months of age, most mutant mice displayed hyperplasia in their forestomach and esophagus, leading to dysplasia and carcinoma formation in older animals. Brca1 mutant mice exhibited increased expression of Redd1, elevated reactive oxygen species and are more sensitive to oxidative stress induced lethality. Upon methyl-N-amylnitrosamine (MNAN) treatment, 70% Brca1 mutant mice developed tumors within 4 months whereas only 14% control animals developed tumor at the same period of the time. Our further analysis revealed that the tumorigenesis is accompanied by the loss of p53 and increased expression of a number of oncogenes, including Cyclin D1, phosphorylated form of Akt, beta-catenin, Runx-2 and c-Myc. These results suggest that Brca1 is involved in renewable organ homeostasis, linking the environmental and genetic factors in carcinogenesis and aging, and providing new insights into genomic instability in organism maintenance and tumorigenesis.
Cao
Liu
L
Genetics of Development and Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Xu
Xiaoling
X
Cao
Longyue L
LL
Wang
Rui-Hong
RH
Coumoul
Xavier
X
Kim
Sang S
SS
Deng
Chu-Xia
CX
D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism*; D002478:Cells, Cultured; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009602:Nitrosamines / Q000633:toxicity; D018384:Oxidative Stress; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D019313:BRCA1 Protein; D002274:Carcinogens, Environmental; D009602:Nitrosamines; D016159:Tumor Suppressor Protein p53; C025033:N-amyl-N-methylnitrosamine