Preferential mammary carcinogenic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in human c-Ha-ras proto-oncogene transgenic rats.

In order to clarify the susceptibility of the Hras128 rat harboring copies of the human c-Ha-ras proto-oncogene to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), Hras128 rats were intragastically treated with 100 mg/kg PhIP 8 times (females) or 80 mg/kg PhIP 10 times (males) over a 9-week period, then sacrificed at weeks 12 and 30. Multiple mammary tumors of adenocarcinoma type were induced in all females, while 83% of treated males developed adenocarcinomas, sarcomas and transitional carcinosarcomas, as evidenced by casein and vimentin immunoreactivity. All tumors examined had mutations in the c-Ha-ras transgene, while the endogenous rat c-Ha-ras gene was intact.

Rapid emergence of mammary preneoplastic and malignant lesions in human c-Ha-ras proto-oncogene transgenic rats: possible application for screening of chemopreventive agents.

For comparison of mammary gland whole mounts with examination of 2 histologic sections of mammary gland, 56 Hras128 rats were intravenously injected with 50 mg/kg body weight of N-methyl-N-nitrosourea at 50 days of age and then sacrificed at days 5, 10, 15, 20, 25, and 56. Comparison of detection sensitivity between the whole mounts and histologic sections revealed no lesions apparent in whole mounts on day 10, although intraductal proliferation was clearly detected in histologic sections in 44% of treated rats. Proliferative lesions were first detected in whole mounts at a 44% incidence on day 15, while intraductal proliferations and atypical hyperplasias were apparent in the sections at 89% and 44% incidences, respectively.

Transgenic rats carrying human c-Ha-ras proto-oncogene are highly susceptible to N-nitrosomethylbenzylamine induction of esophageal tumorigenesis.

A transgenic rat line carrying three copies of the human c-Ha-ras proto-oncogene, including its own promoter region, has been established in our laboratory (Hras128 rats), and shown to be highly susceptible to induction of mammary and urinary bladder tumors. Mutation analysis of induced lesions indicated the majority to contain some but not all cells with transgene mutation. In the present study, the susceptibility of Hras128 rats to N-nitrosomethylbenzylamine (NMBA) induction of esophageal tumors was examined with a similar mutation analysis of the transgenes.

Enhanced skin carcinogenesis in cyclin D1-conditional transgenic mice: cyclin D1 alters keratinocyte response to calcium-induced terminal differentiation.

Cyclin D1 is a critical gene involved in the regulation of progression through the G(1) phase of the cell cycle, thereby contributing to cell proliferation. Gene amplification and abnormal expression of Cyclin D1 have been described in several human cancers. To understand their biological significance in skin carcinogenesis, we established Cyclin D1-conditional transgenic mice with C57BL/6J background, in which skin-specific overexpression of Cyclin D1 transgene was observed.

HST-1/FGF-4 gene activation induces spermatogenesis and prevents adriamycin-induced testicular toxicity.

We previously demonstrated expression of the HST-1/FGF-4 gene in the testis of normal adult animals, which suggests its possible role in spermatogenesis. For an understanding of its functional significance in the testis, conditional transgene expression was used. Precise genetic switches can be efficiently generated in a straightforward manner using adenovirus-carrying Cre recombinase, which means our new strategies promise to contribute substantially to a better and prompt understanding of the functions of genes in vivo by controlling the expression of any gene to any organ at any desired time.