Harvey ras Results in a Higher Frequency of Mammary Carcinomas than Kirsten ras after Direct Retroviral Transfer into the Rat Mammary Gland¹

Exclusive activation of either the Harvey-, Kirsten-, or N-ras gene is often found in human and rodent cancers, although the mechanisms responsible for tissue-specific ras gene activation are poorly understood. In this study, the contribution of ras gene expression and Ras protein activity to the tissue-specificity of ras gene activation was investigated using the rat mammary carcinogenesis model where ras activation, when it occurs, is exclusively in the Harvey ras gene. Differential ras gene expression was examined in mammary tissue from virgin, pregnant, and lactating rats. Harvey ras expression was 1.5–2-fold higher than Kirsten ras or N-ras at each adult stage of development, with the highest ras levels expressed during pregnancy. The modest difference in total mRNA expression found between the independent members of the ras gene family is unlikely to fully account for the exclusive tissue-specificity of Harvey ras activation observed in rat mammary carcinogenesis. Thus, the role of Ras protein specificity was studied by infecting the mammary gland of virgin rats in situ with replication-defective retroviral vectors expressing either the activated or wild-type forms of Harvey- or Kirsten-ras. A 7-14-fold higher number of mammary carcinomas was observed after infection with vectors expressing the G35 to A activated Harvey ras gene product compared with those expressing G35 to A activated Kirsten ras. Mammary carcinomas also developed from infusion of vectors expressing wild-type Harvey ras, but not wild-type Kirsten ras. These data suggest the importance of the Ras protein itself in determining the specificity of the highly homologous Ras family members in organ-specific carcinogenesis.