ARHGAP18 downregulation by miR-200b suppresses metastasis of triple-negative breast cancer by enhancing activation of RhoA

Brock Humphries, Zhishan Wang, Yunfei Li, Jing Ru Jhan, Yiguo Jiang, Chengfeng Yang

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Rho GTPases activated in cancer cells drive proliferation, migration, and metastasis. Thus, RhoGAP proteins, which negatively regulate Rho GTPases, are generally thought to function as tumor suppressors. Here this expectation was challenged by characterization of ARHGAP18, a RhoGAP family member that is selectively overexpressed in highly migratory triple-negative breast cancer (TNBC) cells. In human breast tumors, higher ARHGAP18 levels associated with worse overall survival, recurrence-free survival, and metastasis-free survival. In TNBC cells, ARHGAP18 deletion increased RhoA activation but reduced growth, migration, and metastatic capacity. Mechanistic investigations revealed that ARH-GAP18 levels were controlled by miR-200b, the enforced expression of which was sufficient to activate RhoA, enhanced formation of focal adhesions and actin stress fibers, and reduced migration and metastasis. Enforced elevation of ARHGAP18 where miR-200b was stably expressed reduced RhoA activity but increased cell migration. Pharmacologic inhibition of the Rho effector kinase ROCK blocked RhoA signaling and reversed the inhibitory effect of miR-200b on cell migration. Finally, ARHGAP18 overexpression or ROCK inhibition was sufficient to overcome metastatic blockade by miR-200b. Taken together, these results define opposing roles for oncogenic ARHGAP18 and tumor suppressive miR-200b in determining TNBC cell migration and metastatic prowess.

Original languageEnglish
Pages (from-to)4051-4064
Number of pages14
JournalCancer Research
Issue number15
StatePublished - Aug 1 2017

Bibliographical note

Funding Information:
This study was supported by a Research Scholar Grant (RGS-15-026-01CSM) from the American Cancer Society to C. Yang. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Publisher Copyright:
©2017 AACR.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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