The Oncogenic Role of RhoGAPs in Basal-Like Breast Cancer

: The basal-like breast cancer (BLBC) subtype accounts for a high percentage of overall breast cancer mortality. The current therapeutic options for BLBC are ineffective; hence, elucidating signaling pathways that drive BLBC growth may identify novel targets for the development of effective therapies. Rho GTPases have previously been implicated in promoting tumor cell proliferation and metastasis. These proteins are inactivated by GTPase-activating proteins (GAPs), which have generally been presumed to act as tumor suppressors. Surprisingly, microarray analysis for the expression of Rho GTPase regulators revealed significant upregulation of several RhoGAP genes in BLBCs. The aim of our research is to characterize the role of two of these RhoGAPs, ArhGAP11A and RacGAP1, in BLBC development. In BLBC cell lines, shRNA-mediated knockdown of ArhGAP11A resulted in significant proliferation defects that were caused via p27Kip1-mediated induction of cell cycle arrest. ArhGAP11A was also found to control cell spreading and migration. RacGAP1 depletion significantly retarded BLBC growth but, in contrast to ArhGAP11A, this was due to the combined effects of cytokinesis failure, p21WAF1/Cip1-mediated pRb inhibition, and the onset of senescence. In summary, we have established that ArhGAP11A and RacGAP1 are both critical to in vitro BLBC growth, consistent with an oncogenic role for these GAPs.