A common goal for potential
cancer therapies is the identification of differences in
protein expression or activity that would allow for the selective targeting of
tumor vs. normal cells. The Ras proto-oncogene family (K-Ras, H-Ras and N-Ras) are amongst the most frequently mutated genes in human
cancers. As a result, there has been substantial effort dedicated to determining which pathways are activated by Ras signaling and, more importantly, which of these contribute to
cancer. Although the most widely studied Ras-regulated signaling pathway is the Raf/
mitogen-activated protein kinase cascade, previous research in model systems has revealed that the
Rac1 GTP-binding protein is also required for Ras-induced
biological responses. However, what have been lacking are rigorous in vivo Rac1 target validation data and a clear demonstration that in Ras-driven hyperplastic lesions, Rac1 activity is increased. Using a combination of genetically-modified mouse models that allow for the tissue-selective activation or deletion of signaling molecules and an activation-state sensitive Rac1 antibody that detects
GTP-bound Rac1, we found that Rac1 contributes to K-Ras induced epidermal
papilloma initiation and growth and that Rac1 activity is elevated by oncogenic K-Ras in vivo. Previously, it was not practical to assess Rac1 activation status in the most commonly used format for clinical
tumor specimens,
formalin-fixed
paraffin embedded (FFPE) tissues samples. However, this study clearly demonstrates that Rac1 is essential for K-Ras driven epithelial cell hyperproliferation and that Rac1 activity is elevated in tissues expressing mutant oncogenic K-Ras, while also characterizing the activation-state specific Rac1-GTP antibody as a probe to examine Rac1 activation status in FFPE samples. Our findings will facilitate further research on the status of Rac1 activity in human
tumors and will help to define the
tumor types of the patient population that could potentially benefit from
therapies targeting Rac activation or downstream effector signaling pathways.