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The Oncogenic Role of RhoGAPs in Basal-Like Breast Cancer

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Technical Report,01 Feb 2014,31 Jan 2016

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University of North Carolina at Chapel Hill Chapel Hill United States

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The basal-like breast cancer BLBC subtype accounts for a high percentage of overall breast cancer mortality. The current therapeutic options for BLBC need improvement 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, RNA-Seq analysis of the Rho GTPase signaling transcriptome revealed high expression 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. Both proteins were highly expressed inhuman BLBC cell lines, and knockdown of either gene resulted in significant defects in the proliferation of these cells. Knockdown of ArhGAP11A caused CDKN1Bp27-mediated cell cycle arrest, whereas RacGAP1-depletion inhibited growth through the combined effects of cytokinesis failure, CDKN1Ap21-mediated RB1 inhibition, and the onset of senescence. Random migration was suppressed or enhanced by the knockdown of ArhGAP11A or RacGAP1, respectively. Cell spreading and levels of GTP-bound RhoA were increased upon depletion of either GAP. We have established that ArhGAP11A andRacGAP1 are both critical drivers of BLBC growth, and propose that RhoGAPs can act as oncogenes in cancer.

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