HA-RAS ONCOGENE ACTIVATION IN MAMMARY-GLANDS OF N-METHYL-N-NITROSOUREA-TREATED RATS GENETICALLY RESISTANT TO MAMMARY ADENOCARCINOGENESIS

被引:39
作者
LU, SJ [1 ]
ARCHER, MC [1 ]
机构
[1] UNIV TORONTO, ONTARIO CANC INST, DEPT MED BIOPHYS, 500 SHERBOURNE ST, TORONTO M4X 1K9, ONTARIO, CANADA
关键词
D O I
10.1073/pnas.89.3.1001
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
A single dose of N-methyl-N-nitrosourea given to sexually immature female Buf/N rats produces a high incidence of mammary adenocarcinomas. A large percentage of these tumors contain the Ha-ras oncogene, activated by a G --> A transition at the second nucleotide of codon 12. Copenhagen rats, on the other hand, are completely resistant to mammary tumor induction by a number of carcinogens, including N-methyl-N-nitrosourea. Here we show, using a sensitive method involving PCR, that codon 12 Ha-ras mutations occur in the mammary glands of both Buf/N and Copenhagen rats 30 days after N-methyl-N-nitrosourea treatment. These mutations were evenly distributed among individual mammary glands and were present in purified mammary epithelial cells. In Buf/N rats, the fraction of cells containing a mutated Ha-ras allele increased by a factor of 10-100 between 30 and 60 days, whereas in Copenhagen rats, there was no such increase during this time period. We conclude that the resistance of the Copenhagen rat to mammary carcinogenesis is not due to a defect in initiation but rather appears to be due to the inability of cells containing a mutated ras allele to undergo sustained clonal expansion.
引用
收藏
页码:1001 / 1005
页数:5
相关论文
共 26 条
[1]   MUTATIONAL SPECIFICITY OF N-METHYL-N-NITROSOUREA IN THE LACI GENE OF ESCHERICHIA-COLI [J].
BURNS, PA ;
GORDON, AJE ;
GLICKMAN, BW .
CARCINOGENESIS, 1988, 9 (09) :1607-1610
[2]   A METHOD TO DETECT RAS POINT MUTATIONS IN SMALL SUBPOPULATIONS OF CELLS [J].
CHEN, J ;
VIOLA, MV .
ANALYTICAL BIOCHEMISTRY, 1991, 195 (01) :51-56
[3]   ORGANOTROPE CARCINOGENE WIRKUNGEN BEI 65 VERSCHIEDENEN N-NITROSO-VERBINDUNGEN AN BD-RATTEN [J].
DRUCKREY, H ;
PREUSSMA.R ;
IVANKOVI.S ;
SCHMAHL, D ;
AFKHAM, J ;
BLUM, G ;
MENNEL, HD ;
MULLER, M ;
PETROPOU.P ;
SCHNEIDE.H .
ZEITSCHRIFT FUR KREBSFORSCHUNG, 1967, 69 (02) :103-&
[4]   DNA METHYL-ADDUCT DOSIMETRY AND O-6-ALKYLGUANINE-DNA ALKYL TRANSFERASE-ACTIVITY DETERMINATIONS IN RAT MAMMARY CARCINOGENESIS BY PROCARBAZINE AND N-METHYLNITROSOUREA [J].
FONG, LYY ;
JENSEN, DE ;
MAGEE, PN .
CARCINOGENESIS, 1990, 11 (03) :411-417
[5]  
GOULD MN, 1986, CANCER RES, V46, P1199
[6]  
GOULD MN, 1989, GENES SIGNAL TRANSDU, P19
[7]  
GULLINO PM, 1975, J NATL CANCER I, V54, P401
[8]  
ISAACS JT, 1991, CANCER RES, V51, P1591
[9]  
ISAACS JT, 1986, CANCER RES, V46, P3958
[10]  
ISAACS JT, 1988, CANCER RES, V48, P2204