Rho GTPase Transcriptome Analysis Reveals Oncogenic Roles for Rho GTPase-activating Proteins in Basal-like Breast Cancers
作者： Campbell D. Lawson , Cheng Fan , Natalia Mitin , Nicole M. Baker , Samuel D. George
DOI: 10.1158/0008-5472.CAN-15-2923
关键词:
摘要: The basal-like breast cancer (BLBC) subtype accounts for a disproportionately high percentage of overall mortality. current therapeutic options BLBC need improvement; hence, elucidating signaling pathways that drive growth may identify novel targets the development effective therapies. Rho GTPases have previously been implicated in promoting tumor cell proliferation and metastasis. These proteins are inactivated by Rho-selective GTPase-activating (RhoGAP), which generally presumed to act as suppressors. Surprisingly, RNA-Seq analysis GTPase transcriptome revealed expression several RhoGAP genes tumors, raising possibility these be oncogenic. To evaluate this, we examined roles two RhoGAPs, ArhGAP11A (also known MP-GAP) RacGAP1 MgcRacGAP), BLBC. Both were highly expressed human lines, knockdown either gene resulted significant defects cells. Knockdown caused CDKN1B/p27-mediated arrest G1 phase cycle, whereas depletion inhibited through combined effects cytokinesis failure, CDKN1A/p21-mediated RB1 inhibition, onset senescence. Random migration was suppressed or enhanced RacGAP1, respectively. Cell spreading levels GTP-bound RhoA increased upon RhoGAP. We established that, via suppression RhoA, both critical drivers growth, propose RhoGAPs can oncogenes cancer. Cancer Res; 76(13); 3826-37. ©2016 AACR.
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