Reduction in the frequency of activated ras oncogenes in rat mammary carcinomas with increasing N-methyl-N-nitrosourea doses or increasing prolactin levels

• Published in: Cancer research (Chicago, Ill.) Vol. 50; no. 14; pp. 4286 - 4290
• Main Authors: ZHANG, R, HAAG, J. D, GOULD, M. N
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-07-1990
• Subjects: Adrenalectomy; Animals; Base Sequence; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Desoxycorticosterone - pharmacology; DNA, Neoplasm - genetics; DNA, Neoplasm - isolation & purification; Dose-Response Relationship, Drug; Female; Gene Expression Regulation - drug effects; Genes, ras; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - pathology; Medical sciences; Methylnitrosourea - toxicity; Molecular Sequence Data; Mutation; Oligonucleotide Probes; Prolactin - blood; Prolactin - physiology; Rats; Rats, Inbred WF; Tumors; Rat; Toxicity; Rodentia; Tumor initiation; Carcinogenesis; Multiple phase; Dose activity relation; Carcinogen; Protein hormone; Vertebrata; Mammalia; Prolactin; Animal; C-Onc gene; Mammary gland; Mechanism of action; Tumor promotion
• ISSN: 0008-5472; 1538-7445

The role of c-Ha-ras-1 oncogene activation in the multistage biological process of N-methyl-N-nitrosourea (NMU)-induced mammary carcinogenesis was investigated. The average yield of NMU-induced mammary tumors in Wistar-Furth rats was altered by modification of either the initiation or promotion/progression stage of carcinogenesis. Initiation was varied by the use of different doses of NMU from 20 to 50 mg/kg. Tumor yield was increased with increasing NMU doses. However, the frequency of mammary tumors with activated c-Ha-ras-1 decreased in a linear fashion with increasing NMU doses. Promotion/progression was varied by increasing prolactin levels starting approximately 2 weeks after NMU administration. This hormonal manipulation increased tumor yield, while reducing the frequency of tumors with activated ras. It is postulated that ras activation represents one of several possible mechanisms by which NMU initiates mammary carcinogenesis. Furthermore, initiated cells without activated ras are more dependent on epigenetic promotional events provided by either prolactin or NMU than are ras-initiated cells.