The mutant forms of KRas, NRas and HRas drive the initiation and progression of 
a number of human cancers, but less is known about the role of WT (wild-type) 
Ras alleles and isoforms in cancer. We used zinc-finger nucleases targeting HRas 
and NRas to modify both alleles of these genes in the mutant KRas-driven Hec1A 
endometrial cancer cell line, which normally expresses WT copies of these genes. 
The disruption of either WT isoform of Ras compromised growth-factor-dependent 
signalling through the ERK (extracellular-signal-regulated kinase) pathway. In 
addition, the disruption of HRas hindered the activation of Akt and subsequent 
downstream signalling. This was associated with decreased proliferation, 
increased apoptosis and decreased anchorage-independent growth in the 
HRas-disrupted cells. However, xenograft tumour growth was not significantly 
affected by the disruption of either NRas or HRas. As expected, deleting the 
mutant allele of KRas abolished tumour growth, whereas deletion of the remaining 
WT copy of KRas increased the tumorigenic properties of these cells; deleting a 
single copy of either HRas or NRas did not mimic this effect. The present study 
demonstrates that the WT copies of HRas, NRas and KRas play unique roles in the 
context of mutant KRas-driven tumours.