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Regions of H- and K-Ras That Provide Organ Specificity/Potency in Mammary Cancer Induction¹

McArdle Laboratory for Cancer Research [K. K., M. N. G.], and Department of Biostatistics and Medical Informatics [M. J. L.], University of Wisconsin-Madison, Madison, Wisconsin 53706

Organ-specific cancers with activated ras oncogenes most often are associated exclusively with only one ras isoform. For example, only H-ras activation is associated with rat mammary cancers. The mechanism underlying this specificity is mostly unknown. We have shown previously that this tissue specificity of Ras isoforms is defined by the Ras protein itself and not by differential gene expression among Ras family members. Here we show that elements in the known domains in the hypervariable region of Ras (amino acids 170–189) interact in part to control this mammary/H-Ras specificity. In addition, these in vivo mammary studies for the first time identify domains in the mostly homologous region of Ras (amino acids 1–169) that strongly influence the oncogenic potency/specificity of H-Ras.

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