Filling GAPs in our knowledge: ARHGAP11A and RACGAP1 act as oncogenes in basal-like breast cancers

Like RAS proteins, the aberrant function of RHO family small GTPases has been implicated in driving cancer development and growth. However, unlike the RAS family, where gain-of-function missense mutations are found in ∼25% of all human cancers, missense mutations are relatively rare in RHO proteins. Instead, altered RHO activity in cancer more commonly arises through the aberrant functions of RHO GTPase regulators. In many cancer types, altered expression and/or mutation of RHO-selective guanine nucleotide exchange factors (RHOGEFs) or GTPase-activating proteins (RHOGAPs), which activate or inactivate RHO GTPases, respectively, is observed. For example, deletion or loss of expression of the RHOA GAP DLC1 is well-established to drive cancer growth. Recently, we identified high expression of 2 RHOGAPs, ARHGAP11A and RACGAP1, in the basal-like breast cancer subtype. Unexpectedly, both of these RHOA GAPs exhibited properties of oncoproteins rather than tumor suppressors, in contrast to DLC1. In this commentary, we summarize our findings and speculate that different RHOA GAPs can play distinct roles in cancer depending on their spatial regulation and cancer type context. We also evaluate our results in light of recently-described cancer genome sequencing studies that have identified loss-of-function mutations of RHOA in specific cancer types.